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Osteoporosis and the Replacement of Cell Populations of the Marrow by Adipose Tissue
... In particular, the BM-MSCs of osteoporosis and osteopenia patients exhibit reduced osteogenic potential and increased BM adiposity [14][15][16][17][18][19]. Furthermore, aging causes a decline in the ability of BM-MSCs to proliferate, form colonies and self-renew [11,20]. ...
... However, the osteogenic potential of SNC has not been investigated. As it has been reported that, during aging, BM-MSCs exhibit a shift towards adipogenesis rather than osteogenesis [14][15][16][17]20,45], and given that more than 50% of orthopaedic procedures are performed on older patients [46], evaluating the osteogenic potential of SNC with BM-MSCs from older donors is essential. Previous in vitro osteogenesis studies of other biomaterials such as PCL nanofibrous mat, graphene-incorporated methacrylate gelatin, and rattan wood have been conducted with BM-MSCs from older donors [47][48][49]. ...
Bone void-filling cements are one of the preferred materials for managing irregular bone voids, particularly in the geriatric population who undergo many orthopedic surgeries. However, bone marrow mesenchymal stem/stromal cells (BM-MSCs) of older-age donors often exhibit reduced osteogenic capacity. Hence, it is crucial to evaluate candidate bone substitute materials with BM-MSCs from the geriatric population to determine the true osteogenic potential, thus simulating the clinical situation. With this concept, we investigated the osteogenic potential of shell nacre cement (SNC), a bone void-filling cement based on shell nacre powder and ladder-structured siloxane methacrylate, using older donor BM-MSCs (age > 55 years) and young donor BM-MSCs (age < 30 years). Direct and indirect cytotoxicity studies conducted with human BM-MSCs confirmed the non-cytotoxic nature of SNC. The standard colony-forming unit-fibroblast (CFU-F) assay and population doubling (PD) time assays revealed a significant reduction in the proliferation potential (p < 0.0001, p < 0.05) in older donor BM-MSCs compared to young donor BM-MSCs. Correspondingly, older donor BM-MSCs contained higher proportions of senescent, β-galactosidase (SA-β gal)-positive cells (nearly 2-fold, p < 0.001). In contrast, the proliferation capacity of older donor BM-MSCs, measured as the area density of CellTrackerTM green positive cells, was similar to that of young donor BM-MSCs following a 7-day culture on SNC. Furthermore, after 14 days of osteoinduction on SNC, scanning electron microscopy with energy-dispersive spectroscopy (SEM-EDS) showed that the amount of calcium and phosphorus deposited by young and older donor BM-MSCs on SNC was comparable. A similar trend was observed in the expression of the osteogenesis-related genes BMP2, RUNX2, ALP, COL1A1, OMD and SPARC. Overall, the results of this study indicated that SNC would be a promising candidate for managing bone voids in all age groups.
... These results suggest that ANAPC1 is important at a particular time point during osteogenic differentiation. Bone loss is also associated with increased adipose tissue in the bone marrow of osteoporosis patients [27]. To determine whether ANAPC1 expression also changes during the adipogenic differentiation of MSCs, ANAPC1 expression was measured during the adipogenic differentiation of MSCs. ...
... Bone loss is also associated with increased adipose tissue in the bone marrow of osteoporosis patients [27]. To determine whether ANAPC1 expression also changes during the adipogenic differentiation of MSCs, ANAPC1 expression was measured during the adipogenic differentiation of MSCs. ...
Genome-wide association studies (GWAS) are one of the most common approaches to identify genetic loci that are associated with bone mineral density (BMD). Such novel genetic loci represent new potential targets for the prevention and treatment of fragility fractures. GWAS have identified hundreds of associations with BMD; however, only a few have been functionally evaluated. A locus significantly associated with femoral neck BMD at the genome-wide level is intronic SNP rs17040773 located in the intronic region of the anaphase-promoting complex subunit 1 (ANAPC1) gene (p = 1.5 × 10−9). Here, we functionally evaluate the role of ANAPC1 in bone remodelling by examining the expression of ANAPC1 in human bone and muscle tissues and during the osteogenic differentiation of human primary mesenchymal stem cells (MSCs). The expression of ANAPC1 was significantly decreased 2.3-fold in bone tissues and 6.2-fold in muscle tissue from osteoporotic patients as compared to the osteoarthritic and control tissues. Next, we show that the expression of ANAPC1 changes during the osteogenic differentiation process of human MSCs. Moreover, the silencing of ANAPC1 in human osteosarcoma (HOS) cells reduced RUNX2 expression, suggesting that ANAPC1 affects osteogenic differentiation through RUNX2. Altogether, our results indicate that ANAPC1 plays a role in bone physiology and in the development of osteoporosis.
... It has been demonstrated that a pathological decrease in bone mineral density is followed by fat accumulation [9][10][11]. Since both osteoblasts and adipocytes originate from MSC, it is expected that the predilection of MSC to differentiate into adipocyte instead of osteoblast lineage is a contributing factor to bone loss. ...
... Since both osteoblasts and adipocytes originate from MSC, it is expected that the predilection of MSC to differentiate into adipocyte instead of osteoblast lineage is a contributing factor to bone loss. The commitment of MSC toward each osteoblast or adipocyte lineage is dependent on specific transcriptional regulators [9,12]. Among these, peroxisome proliferator-activated receptor gamma (PPAR-γ) and CCAAT enhancer binding protein α (C/EBPα) are critical regulators of adipogenesis [13]. ...
Osteoarticular injury is the most common presentation of active brucellosis in humans. Osteoblasts and adipocytes originate from mesenchymal stem cells (MSC). Since those osteoblasts are bone-forming cells, the predilection of MSC to differentiate into adipocytes or osteoblasts is a potential factor involved in bone loss. In addition, osteoblasts and adipocytes can be converted into each other according to the surrounding microenvironment. Here, we study the incumbency of B. abortus infection in the crosstalk between adipocytes and osteoblasts during differentiation from its precursors. Our results indicate that soluble mediators present in culture supernatants from B. abotus-infected adipocytes inhibit osteoblast mineral matrix deposition in a mechanism dependent on the presence of IL-6 with the concomitant reduction of Runt-related transcription factor 2 (RUNX-2) transcription, but without altering organic matrix deposition and inducing nuclear receptor activator ligand kβ (RANKL) expression. Secondly, B. abortus-infected osteoblasts stimulate adipocyte differentiation with the induction of peroxisome proliferator-activated receptor γ (PPAR-γ) and CCAAT enhancer binding protein β (C/EBP-β). We conclude that adipocyte–osteoblast crosstalk during B. abortus infection could modulate mutual differentiation from its precursor cells, contributing to bone resorption.
... Aging triggers a decrease in trabecular bone mass and an increase in bone marrow adipocytes, both of which are more pronounced in patients with osteoporosis (5,6). However, during senile osteoporosis, the rate of adipogenesis increases, while that of osteogenesis decreases (7). ...
... Increased bone marrow fat is accompanied by age-dependent bone loss, as well as bone loss caused by estrogen deficiency and glucocorticoid excess (6,42). Thiazolidinediones, activators of the key adipogenic transcription factor PPARγ, increase marrow adipocytes, decrease bone formation, and cause loss of trabecular and endocortical bone (43,44). ...
The central physiological role of the bone marrow renders the bone marrow stromal cells (BMSCs) particularly sensitive to aging. With bone aging, BMSCs acquire a differentiation potential bias in favor of adipogenesis over osteogenesis, and the underlying molecular mechanisms remain unclear. Herein, we investigated the factors underlying age-related changes in the bone marrow, and their roles in BMSCs differentiation. Antibody array revealed that C-C motif chemokine ligand 3 (CCL3) accumulation occurred in the serum of naturally aged mice along with bone aging phenotypes, including bone loss, bone marrow adiposity, and imbalanced BMSCs differentiation. In vivo Ccl3 deletion could rescue these phenotypes in aged mice. CCL3 improved the adipogenic differentiation potential of BMSCs, with a positive feedback loop between CCL3 and C/EBPα. CCL3 activated C/EBPα expression via STAT3, while C/EBPα activated CCL3 expression through direct promoter binding, facilitated by DNA hypo-methylation. Moreover, CCL3 inhibited BMSCs osteogenic differentiation potential by blocking β-catenin activity mediated by ERK-activated DKK-1 upregulation. Blocking CCL3 in vivo via neutralization antibodies ameliorated trabecular bone loss and bone marrow adiposity in aged mice. This study provides insights regarding age-related bone loss and bone marrow adiposity pathogenesis, and lays a foundation for the identification of new targets for senile osteoporosis treatment.
... An increased bone marrow adipose tissue content may be related to a lower bone mass. People with osteoporosis have a higher fat content and greater number of fat cells in their bone marrow than healthy people [2,3]. This disorder is caused by the abnormal differentiation of adipocytes and osteoblast progenitor cells. ...
... Yunhui Zhang, Wenjie Liu, Weiquan Yuan have contributed equally to this work. into adipocytes [2,8]. The number of adipocytes in the bone marrow increases abnormally, while the number of osteoblasts decreases, resulting in bone mass loss [9]. ...
An imbalance of human mesenchymal stem cells (hMSCs) adipogenic and osteogenic differentiation is crucial in the pathogenesis of osteoporosis, and elucidation of the underlying mechanism is urgently needed. APPL1, an adaptor protein of the adiponectin receptor, was recently shown to be closely related to bone mass. However, the role of APPL1 in the imbalance of hMSC differentiation in osteoporosis is unclear. Therefore, we aimed to explore the mechanisms by which APPL1 alters hMSCs adipogenic differentiation in osteoporosis. Here, we found that APPL1 expression was downregulated in elderly patients with osteoporosis and in mouse osteoporosis model. APPL1 negatively regulated hMSC adipogenic differentiation in vivo and in vitro. Mechanistically, by enhancing ubiquitination-mediated Myoferlin degradation, downregulated APPL1 expression increased the risk of lysosome dysfunction during hMSCs adipogenic differentiation. Lysosomal dysfunction inhibited autophagy flux by suppressing autophagosome degradation and promoted hMSC differentiation towards the adipocyte lineage. Our findings suggest that APPL1/Myoferlin downregulation promoted hMSCs adipogenic differentiation by inhibiting autophagy flux, further impairing the balance of hMSCs adipogenic and osteogenic differentiation in osteoporosis; the APPL1/ Myoferlin axis may be a promising diagnostic and therapeutic target for osteoporosis.
... Both excess synthetic and endogenous GCs are known to cause bone loss (47). In general, an inverse relationship exists between BMAT volume and bone mass, including in patients with anorexia nervosa (48)(49)(50). Together these results suggest that excess GC during CR may lead to increased BMAT and subsequent bone loss (51,52). Indeed, work from Pierce et al. have shown that GR-deficiency in Osx-expressing cells led to loss of cortical and trabecular bone mass in mice fed ad libitum or CR (53). ...
Introduction
Unlike white adipose tissue depots, bone marrow adipose tissue (BMAT) expands during caloric restriction (CR). Although mechanisms for BMAT expansion remain unclear, prior research suggested an intermediary role for increased circulating glucocorticoids.
Methods
In this study, we utilized a recently described mouse model (BMAd-Cre) to exclusively target bone marrow adipocytes (BMAds) for elimination of the glucocorticoid receptor (GR) (i.e. Nr3c1) whilst maintaining GR expression in other adipose depots.
Results
Mice lacking GR in BMAds (BMAd-Nr3c1 -/-) and control mice (BMAd-Nr3c1 +/+) were fed ad libitum or placed on a 30% CR diet for six weeks. On a normal chow diet, tibiae of female BMAd-Nr3c1-/- mice had slightly elevated proximal trabecular metaphyseal bone volume fraction and thickness. Both control and BMAd-Nr3c1-/- mice had increased circulating glucocorticoids and elevated numbers of BMAds in the proximal tibia following CR. However, no significant differences in trabecular and cortical bone were observed, and quantification with osmium tetroxide and μCT revealed no difference in BMAT accumulation between control or BMAd-Nr3c1 -/- mice. Differences in BMAd size were not observed between BMAd-Nr3c1-/- and control mice. Interestingly, BMAd-Nr3c1-/- mice had decreased circulating white blood cell counts 4 h into the light cycle.
Discussion
In conclusion, our data suggest that eliminating GR from BMAd has minor effects on bone and hematopoiesis, and does not impair BMAT accumulation during CR.
... At present, there is no diagnostic standard of HU value for the diagnosis of low bone mass or osteoporosis, and the examination sites and values obtained by each study are not uniform. In recent years, some scholars have found that the process of osteoporosis is accompanied by local fat cells invading the bone and replacing trabecular bone, which weakens the bone structure [30]. Meanwhile, Shen W et al. [12] found that the degree of infiltration of adipocytes in the bone marrow could reflect osteoporosis. ...
Objective
The traditional VBQ scoring method may lead to overestimation due to the concentration of intravertebral fat and vascular structures in the posterior half of vertebral bodies, potentially resulting in false-positive outcomes. This study aims to modify the measurement method of VBQ score (Modified-VBQ) and evaluate its effectiveness in evaluating bone quality of lumbar degenerative diseases.
Methods
Retrospective analysis was conducted on clinical data from patients undergoing lumbar surgery for degenerative diseases between September 2022 and September 2023. Preoperative lumbar t1-weighted Magnetic resonance imaging was used for both modified and traditional VBQ scoring. Computed tomography (CT) images and dual-energy X-ray absorptiometry (DEXA) data were collected through the picture archiving and communication system. The effectiveness of the modified VBQ score was evaluated, considering P < 0.05 as statistically significant.
Results
The study included 212 patients, revealing a significant difference between the modified VBQ and VBQ scores (P < 0.0001). Notably, patients with a history of hyperlipidemia exhibited a significant difference between the two scores (P = 0.0037). The area under the ROC curve (AUC) for the modified VBQ was 0.86, surpassing the VBQ score (AUC = 0.74). Linear regression analysis demonstrated a moderate to strong correlation between the modified VBQ and DEXA T-score (r = − 0.49, P < 0.0001) and a high correlation with CT Hounsfield units (HU) values (r = − 0.60, P < 0.0001).
Conclusion
The modified VBQ score provides a simple, effective, and relatively accurate means of assessing bone quality in lumbar degenerative diseases. Preoperative implementation of the modified VBQ score facilitates rapid screening for patients with abnormal bone quality.
... 8, 15,16 The vertebral bone quality score was based on the nding that the adipose tissue content increased as the vertebral body became osteoporotic. 17 The signal intensity of the vertebral body measured on the T1-weighted image increased as the fat in ltration increased, thus re ecting the bone quality of the medullary portion of the vertebral body. Further studies have demonstrated that the VBQ score had moderate correlation with BMD measured by quantitative computed tomography. ...
Objective
To investigate the predictive ability of the MRI-based vertebral bone quality (VBQ) score for pedicle screw loosening following instrumented transforaminal lumbar interbody fusion (TLIF).
Methods
Data from patients who have received one or two-level instrumented TLIF from February 2014 to March 2015 were retrospectively collected. Pedicle screw loosening was diagnosed when the radiolucent zone around the screw exceeded 1mm in plain radiographs. The T1-weighted MRI sagittal images were used for calculation of the VBQ score. Univariate analysis and multivariate binary logistic regression analysis were performed. Receiver operating characteristic curve analysis assessed the predictive ability of the VBQ score on screw loosening.
Results
Among the included 211 patients, 75 of them (35.55%) had pedicle screw loosening at the 24 month follow-up. Multivariable logistic regression analyses demonstrated that higher VBQ score (OR: 27.887 ± 0.514 ,95% CI: 10.189–76.326), male sex (female to male 0.323 ± 0.483, 0.126–0.833), and longer fusion length (2.578 ± 0.545, 1.166–5.701) were significant influencing factors for pedicle screw loosening. The VBQ score significantly predicted screw loosening with an accuracy of 78.9%.
Conclusions
A higher VBQ score was an independent risk factor for pedicle screw loosening following instrumented TLIF. The MRI-based VBQ score showed good predictive ability for screw loosening and could be used as an alternative option for preoperative bone quality evaluation.
... Increased marrow adipose tissue (MAT) volume is recognized as a prominent feature of osteoporosis, which accelerates bone loss due to the anti-osteogenic activity of secreted fatty acids, adipokines and RANKL (Meunier et al., 1971;Rosen and Bouxsein, 2006;Botolin and McCabe, 2007;Zhang et al., 2011;Sadie-Van Gijsen et al., 2013;Devlin and Rosen, 2015). This observation has implicated skeletal stem/ progenitor cells (SSPCs), which serve as the main precursor of osteoblasts and adipocytes in adult bone marrow (BM), as important players in osteoporosis Panes et al., 2016;Yue et al., 2016). ...
Introduction: In the rapidly aging U.S. population, age-induced bone loss (senile osteoporosis) represents a major public health concern that is associated with a significant increased risk for low trauma fragility fractures, which are debilitating to patients, cause significant morbidity and mortality, and are costly to treat and manage. While various treatments exist to slow bone loss in osteoporosis patients, these suffer from poor tolerability and label restrictions that limit their overall effectiveness. Over the past decade, skeletal stem/progenitor cells (SSPCs), which are the main precursor of osteoblasts and adipocytes in adult bone marrow (BM), have emerged as important players in osteoporosis.
Methods: Age-induced skeletal pathology was quantified in elderly (24-month-old) vs. mature (3-month-old) mice by micro-CT and changes in SSPC abundance in the BM of these mice was quantified by fluorescence-activated cell sorting (FACS). SSPCs from elderly vs. mature mice were also analyzed by RNA-Seq to identify differentially expressed genes (DEGs), and gain and loss-of-function studies were performed in human BM-derived mesenchymal stromal cells (BM-MSCs) to assess A2M function.
Results: Elderly mice were shown to exhibit significant age-induced skeletal pathology, which correlated with a significant increase in SSPC abundance in BM. RNA-seq analysis identified alpha-2-macroglobulin (A2M), a pan-protease inhibitor that also binds inflammatory cytokines, as one of the most downregulated transcripts in SSPCs isolated from the BM of elderly vs. mature mice, and silencing of A2M expression in human BM-MSCs induced their proliferation and skewed their lineage bifurcation toward adipogenesis at the expense of osteogenesis thereby recapitulating critical aspects of age-induced stem cell dysfunction.
Conclusion: These findings identify A2M as a novel disease modifying protein in osteoporosis, downregulation of which in bone marrow promotes SSPC dysfunction and imbalances in skeletal homeostasis.
... plays a vital role in maintaining skeletal homeostasis. Prolonged use of thiazolidinediones, which are synthetic agents that activate PPARγ, has been correlated with an increased incidence of fracture in individuals with diabetes mellitus [27,28]. The study findings revealed that patients with osteoporosis exhibited an increased number of adipose cells in the bone marrow. ...
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a rare but severe adverse effect that can occur as a result of bisphosphonate treatment. This study aimed to examine the relationship between PPARγ and PPARGC1A polymorphisms and the BRONJ development in female osteoporosis patients undergoing bisphosphonate treatment. We prospectively conducted this nested case–control study at the Ewha Womans University Mokdong Hospital between 2014 and 2018. We assessed five single-nucleotide polymorphisms (SNPs) of PPARγ and six SNPs of PPARGC1A and performed a multivariable logistic regression analysis to determine the independent risk factors for developing BRONJ. There were a total of 123 patients included in this study and 56 patients (45.5%) developed BRONJ. In the univariate analysis, PPARGC1A rs2946385 and rs10020457 polymorphisms were significantly associated with BRONJ (p = 0.034, p = 0.020, respectively), although the results were not statistically significant in the multivariable analysis. Patients with the combined genotypes of GG in both PPARγ rs1151999 and PPARGC1A rs2946385 showed a 3.03-fold higher risk of BRONJ compared to individuals with other genotype combinations after adjusting for confounders (95% confidence interval (CI): 1.01–9.11). Old age (≥70 years) and duration of bisphosphonate use (≥60 months) increased the risk of BRONJ. The area under the receiver operating characteristic curve for the predicted probability was 0.78 (95% CI: 0.69–0.87, p < 0.001), demonstrating a satisfactory level of discriminatory power. Our study elucidated that PPARγ and PPARGC1A polymorphisms were interactively associated with BRONJ development. These results have potential implications for tailoring personalized treatments for females undergoing bisphosphonate therapy for osteoporosis.
... Patients with VBQ scores above the cutoff value were 2.7 times more likely to suffer from subsidence than those with lower VBQ scores. When bone mineral density is decreased, bone trabeculae are replaced by infiltrating adipocytes, resulting in increased bone fragility [42]. Moreover, the signal intensity of fat tissue is higher than that of bone tissue on T1-weighted images. ...
Purpose:
This is the first study to evaluate the predictive value of the vertebral bone quality (VBQ) score on cage subsidence after transforaminal lumbar interbody fusion (TLIF) in a Chinese population using the spinal quantitative computed tomography (QCT) as the clinical standard. Meanwhile, the accuracy of the MRI-based VBQ score in bone mineral density (BMD) measurement was verified.
Methods:
We performed a retrospective study of patients who underwent single-level TLIF from 2015 to 2020 with at least 1 year of follow-up. Cage subsidence was measured using postoperative radiographic images based on cage protrusion through the endplates more than 2 mm. The VBQ score was measured on T1-weighted MRI. The results were subjected to statistical analysis.
Results:
A total of 283 patients (61.1% of female) were included in the study. The subsidence rate was with 14.1% (n = 40), and the average cage subsidence was 2.3 mm. There was a significant difference in age, sex, VBQ score and spinal QCT between the subsidence group and the no-subsidence group. The multivariable analysis demonstrated that only an increased VBQ score (OR = 2.690, 95% CI 1.312-5.515, p = 0.007) and decreased L1/2 QCT-vBMD (OR = 0.955, 95% CI 0.933-0.977, p < 0.001) were associated with an increased rate of cage subsidence. The VBQ score was found to be moderately correlated with the spinal QCT (r = -0.426, p < 0.001). The VBQ score was shown to significantly predict cage subsidence, with an accuracy of 82.5%.
Conclusion:
Our findings indicate that the MRI-based VBQ score is a significant predictor of cage subsidence and could be used to assess BMD.
... Osteoporosis is the most common skeletal disorder characterized by low mineral density and bone structure deterioration, leading to increased fracture risk in the ageing population. In addition to the well-established concept that osteoporosis is caused by the imbalance between osteoblasts and osteoclasts [1,2], growing evidence suggests the involvement of aberrant lineage allocation of bone marrow-derived mesenchymal stromal cells (BMSCs) [3,4]. BMSCs are multipotent cells with the ability of self-renewal and multiple lineage differentiation including osteoblasts and adipocytes [5,6]. ...
Background
Recent evidence suggests that accumulation of marrow adipose tissue induced by aberrant lineage allocation of bone marrow-derived mesenchymal stromal cells (BMSCs) contributes to the pathophysiologic processes of osteoporosis. Although master regulators of lineage commitment have been well documented, molecular switches between osteogenesis and adipogenesis are largely unknown.
Methods
HSPB7 gene expression during osteogenic and adipogenic differentiation of BMSCs was evaluated by qPCR and Western blot analyses. Lentiviral-mediated knockdown or overexpression of HSPB7 and its deletion constructs were used to assess its function. The organization of cytoskeleton was examined by immunofluorescent staining. ALP activity, calcium assay, Alizarin Red S staining and Oil Red O staining were performed in vitro during osteoblast or adipocyte differentiation. SB431542 and Activin A antibody were used to identify the mechanism of Activin A in the regulation of osteogenic differentiation in BMSCs.
Results
In this study, we identified HSPB7 capable of oppositely regulating osteogenic and adipogenic differentiation of BMSCs. HSPB7 silencing promoted adipogenesis while reducing osteogenic differentiation and mineralization. Conversely, overexpression of HSPB7 strongly enhanced osteogenesis, but no effect was observed on adipogenic differentiation. Deletion of the N-terminal or C-terminal domain of HSPB7 led to decreased osteoblastic potency and mineralization. Mechanistically, our data showed that Activin A is a downstream target participating in HSPB7 knockdown-mediated osteogenic inhibition.
Conclusions
Our findings suggest that HSPB7 plays a positive role in driving osteoblastic differentiation, and with the capability in maintaining the osteo-adipogenesis balance. It holds great promise as a potential therapeutic target in the treatment of bone metabolic diseases.
... Previous studies indicated that PPARγ (the principal transcription factor of adipogenesis) suppresses MSC osteogenic differentiation and thus contributes to osteoporosis progression [47]. MSCs exhibit a bias toward adipogenesis in the bone disorders of aging [48]. We Oil Red O Staining showed that LAMP2A inhibited adipogenesis. ...
Chaperone-mediated autophagy (CMA) plays multiple roles in cell metabolism. We found that lysosome-associated membrane protein type 2A (LAMP2A), a crucial protein of CMA, plays a key role in the control of mesenchymal stem cell (MSC) adipo-osteogenesis. We identified a differentially expressed CMA gene (LAMP2) in GEO datasets (GSE4911 and GSE494). Further, we performed co-expression analyses to define the relationships between CMA components genes and other relevant genes including Col1a1, Runx2, Wnt3 and Gsk3β. Mouse BMSCs (mMSCs) exhibiting Lamp2a gene knockdown (LA-KD) and overexpression (LA-OE) were created using an adenovirus system; then we investigated LAMP2A function in vitro by Western blot, Oil Red staining, ALP staining, ARS staining and Immunofluorescence analysis. Next, we used a modified mouse model of tibial fracture to investigate LAMP2A function in vivo. LAMP2A knockdown in mMSCs decreased the levels of osteogenic-specific proteins (COL1A1 and RUNX2) and increased those of the adipogenesis markers PPARγ and C/EBPα; LAMP2A overexpression had the opposite effects. The active-β-catenin and phospho-GSK3β (Ser9) levels were upregulated by LAMP2A overexpression and downregulated by LAMP2A knockdown. In the mouse model of tibial fracture, mMSC-overexpressing LAMP2A improved bone healing, as demonstrated by microcomputed tomography and histological analyses. In summary, LAMP2A positively regulates mMSC osteogenesis and suppresses adipo-osteogenesis, probably via Wnt/β-catenin/GSK3β signaling. LAMP2A promoted fracture-healing in the mouse model of tibial fracture.
Key messages
• LAMP2 positively regulates the mBMSCs osteogenic differentiation.
• LAMP2 negatively regulates the mBMSCs adipogenic differentiation.
• LAMP2 regulates mBMSCs osteogenesis via Wnt/β-catenin/GSK3β signaling pathway.
• LAMP2 overexpression mBMSCs promote the fracture healing.
... La fraction lipidique au sein de la moelle hématopoïétique des vertèbres lombaires augmente de près de 2,5% chez la femme après 60 jours d'alitement . Cette augmentation correspond à l'équivalent de quatre années d'évolution physiologique (Meunier et al., 1971;Gurevitch et al., 2007) et était toujours visible un an après la fin du protocole. ...
Français: Les études de simulation de microgravité ont mis en évidence des adaptations du métabolisme intermédiaire et une diminution de la flexibilité métabolique (c-à-d la capacité à ajuster l’utilisation des substrats en fonction des changements de leur disponibilité), pouvant entrainer des conséquences néfastes sur la performance et la santé des astronautes. Dans le contexte de la nouvelle phase exploratoire spatiale, ce travail de thèse a cherché à combler les lacunes actuelles pour mieux comprendre l’impact de la microgravité sur la flexibilité métabolique et les mécanismes cellulaires et moléculaires sous-jacents. Nous avons montré chez des hommes sains que seuls 5 jours d’exposition à la microgravité par immersion sèche induisent une diminution de la sensibilité à l’insuline, une hypertriglycéridémie et une accumulation de lipides hépatiques. Au niveau du muscle squelettique, une altération de la voie de signalisation de l’insuline ainsi qu’une réduction de la flexibilité métabolique au glucose ont été notées. Cette dernière semble précéder l’altération de la flexibilité métabolique au niveau du corps entier. Chez des astronautes ayant séjourné au moins 3 mois à bord de la station spatiale internationale, la flexibilité métabolique et l’oxydation postprandiale des substrats n’ont pas été affectées en moyenne. Toutefois les variabilités inter-individuelles ont mis en évidence des relations entre la flexibilité métabolique, l’exercice, le régime alimentaire et les changements de composition corporelle. Ces résultats apportent de nouveaux éléments pour aider à la préparation des futures missions de longue durée. Enfin, ces travaux ont des retombées sur terre en aidant à mieux comprendre les effets de l’inactivité physique sur le développement de pathologies métaboliques.
Anglais: Simulated microgravity studies have shown adaptations of intermediate metabolism and a decrease in metabolic flexibility (i.e., the ability to adjust substrate utilization according to changes in their availability), which can have adverse consequences on astronaut performance and health. In the context of the new space exploratory phase, this thesis work aimed at filling the current gaps to better understand the impact of microgravity on metabolic flexibility and the underlying cellular and molecular mechanisms. We have shown in healthy men that only 5 days of exposure to simulated microgravity by dry immersion induce a decrease in insulin sensitivity, hypertriglyceridemia, and an accumulation of hepatic lipids. At the level of skeletal muscle, an alteration of the insulin signaling pathway as well as a reduction of the metabolic flexibility to glucose have been noted. The latter seems to precede the alteration of metabolic flexibility at the level of the whole body. In astronauts who spent at least 3 months on the International Space Station, metabolic flexibility and postprandial oxidation of substrates were not affected on average. However, inter-individual variabilities revealed relationships between metabolic flexibility, exercise, diet, and body composition changes. These results provide new insights to assist in the preparation of future long-duration missions. Finally, this work has implications on earth by providing a better understanding of the effects of physical inactivity on the development of metabolic pathologies.
... Osteoporoz (OP), azalmış kemik kütlesi ve kemik dokusunun bozulması ile karakterizedir, bu da kemik gücünde azalmaya ve kırılma eğilimine yol açar. Menopoz sonrası kadınların üçte birinden fazlasını ve 60 yaş üstü erkeklerin %10-16'sını etkileyen yaygın bir hastalıktır (1,2). Kemik kütlesi birikimi intrauterin yaşamda başlar ve büyüme periyodu boyunca devam eder, böylece kemik kütlesi insanlarda yaşamın üçüncü on yılında zirveye ulaşır. ...
Osteoporosis (OP) is a systemic disease characterized by low bone mass and deterioration of the microarchitecture of bone tissue, resulting in increased bone fragility and fracture tendency. Environmental factors early in life, including the prenatal period, can affect bone mass later in life and thus the risk of OP. Epigenetics mainly plays a post-transcriptional regulatory role and has important functions in the biological signal-regulatory pathway. Epigenetic mechanisms play an important role in the differentiation of bone cells, osteoblasts, and osteoclasts, which are responsible for bone formation and bone resorption. Several studies have shown some differentially methylated genes in patients with OP. The abnormal epigenetic regulation can lead to a number of bone metabolism-related diseases such as OP. These include genes for the Wnt pathway, an important regulator of osteoblast differentiation, and other genes involved in skeletal development. Similarly, some MicroRNA’s may be differentially expressed in these patients. However, it is recommended that these results should be replicated in other cohorts. Unlike the genome, the epigenome is cell-specific and changes with aging and environmental factors. Therefore, the design and interpretation of epigenetic epidemiology studies pose a number of practical challenges. Epigenetic mechanisms play an important role in the differentiation of bone cells, osteoblasts, and osteoclasts, which are responsible for bone formation and bone resorption.
... BMAT is unique because it is the only tissue where BMAds and bone cells are juxtaposed. As first noted by Meunier [12], increased BMAT is seen in osteoporosis. Since then, increased interest in BMAT has led to several important findings [13,14]. ...
Sclerostin is a Wnt signaling pathway inhibitor that negatively regulates bone formation. Bone-marrow-derived stromal cell (BMSC) differentiation is influenced by the Wnt pathway, leading to the hypothesis that higher levels of sclerostin might be associated with an increase in bone marrow adiposity (BMA). The main purpose of this study was to determine whether a relationship exists between circulating sclerostin and BMA in post-menopausal women with and without fragility fractures. The relationships between circulating sclerostin and body composition parameters were then examined. The outcomes measures included vertebral and hip proton density fat fraction (PDFF) using the water fat imaging (WFI) MRI method; DXA scans; and laboratory measurements, including serum sclerostin. In 199 participants, no significant correlations were found between serum sclerostin and PDFF. In both groups, serum sclerostin was correlated positively with bone mineral density (R = 0.27 to 0.56) and negatively with renal function (R = −0.22 to −0.29). Serum sclerostin correlated negatively with visceral adiposity in both groups (R = −0.24 to −0.32). Serum sclerostin correlated negatively with total body fat (R = −0.47) and appendicular lean mass (R = −0.26) in the fracture group, but not in the controls. No evidence of a relationship between serum sclerostin and BMA was found. However, serum sclerostin was negatively correlated with body composition components, such as visceral adiposity, total body fat and appendicular lean mass.
... The accumulation process starts around the third or fourth decade of life, and thus appears to be independent of estrogen levels. Both studies using human and animal bone samples have reported an increased amount of marrow fat in aging bone (Duque et al., 2009;Meunier, Aaron, Edouard, & Vignon, 1971;Verma, Rajaratnam, Denton, Hoyland, & Byers, 2002). A long-standing mechanistic hypothesis has revolved around the fact that bone marrow adipocytes and osteoblasts arise from common multipotent MSCs, and commitment to each cell lineage occurs in a mutually exclusive fashion (Berry, Rodeheffer, Rosen, & Horowitz, 2015;Horowitz et al., 2017). ...
Animal models are fundamental to advance our knowledge of the underlying pathophysiology of bone loss and to study pharmaceutical countermeasures against it. The animal model of post-menopausal osteoporosis from ovariectomy is the most widely used preclinical approach to study skeletal deterioration. However, several other animal models exist, each with unique characteristics such as bone loss from disuse, lactation, glucocorticoid excess, or exposure to hypobaric hypoxia. The present review aimed to provide a comprehensive overview of these animal models to emphasize the importance and significance of investigating bone loss and pharmaceutical countermeasures from perspectives other than post-menopausal osteoporosis only. Hence, the pathophysiology and underlying cellular mechanisms involved in the various types of bone loss are different, and this might influence which prevention and treatment strategies are the most effective. In addition, the review sought to map the current landscape of pharmaceutical countermeasures against osteoporosis with an emphasis on how drug development has changed from being driven by clinical observations and enhancement or repurposing of existing drugs to today's use of targeted anti-bodies that are the result of advanced insights into the underlying molecular mechanisms of bone formation and resorption. Moreover, new treatment combinations or repurposing opportunities of already approved drugs with a focus on dabigatran, parathyroid hormone and abaloparatide, growth hormone, inhibitors of the activin signaling pathway, acetazolamide, zoledronate, and romosozumab are discussed. Despite the considerable progress in drug development, there is still a clear need to improve treatment strategies and develop new pharmaceuticals against various types of osteoporosis. The review also highlights that new treatment indications should be explored using multiple animal models of bone loss in order to ensure a broad representation of different types of skeletal deterioration instead of mainly focusing on primary osteoporosis from post-menopausal estrogen deficiency.
... Previous studies have revealed that bone mass is inversely related to fat mass [31]; if the adipogenic process of PDLSCs is promoted instead of the osteogenic process, the recovery of defective periodontal tissue would be more challenging [32]. To explore the influence of c-di-AMP on the adipogenic differentiation of PDLSCs, we performed Oil Red O staining and western blot analysis. ...
Cyclic di-adenosine monophosphate (c-di-AMP) is a bacterial second messenger that can be recognized by infected host cells and activate the immunoinflammatory response. The purpose of this study is to demonstrate the effect of c-di-AMP on the differentiation of human periodontal ligament stem cells (hPDLSCs) and its underlying mechanisms. In the present study, we find that the gingival crevicular fluid (GCF) of patients with chronic periodontitis has a higher expression level of c-di-AMP than that of healthy people. In vitro, c-di-AMP influences the differentiation of hPDLSCs by upregulating Toll-like receptors (TLRs); specifically, it inhibits osteogenic differentiation by activating NF-κB and ERK/MAPK and promotes adipogenic differentiation through the NF-κB and p38/MAPK signaling pathways. Inhibitors of TLRs or activated pathways reduce the changes induced by c-di-AMP. Our results establish the potential correlation among bacterial c-di-AMP, periodontal tissue homeostasis and chronic periodontitis pathogenesis.
... (7) This inverse relationship with bone mineral density is well-documented and potentially makes bone marrow fat a therapeutic target for osteoporosis. (8,9) Although the quantification of bone marrow fat previously required invasive bone biopsies, it can now reliably be quantified by noninvasive techniques including magnetic resonance imaging (MRI) and spectroscopy. (10) To date, only long-term changes in bone marrow fat have been investigated. ...
... At the bone tissue level, OP is characterized by increased bone porosity which results from the loss of balance between bone formation and bone resorption as aging, disuse, inflammatory diseases, hormonal imbalance or the effect of glucocorticoids impair the ability of osteoblast to keep up with the pace of bone resorption by the osteoclasts (4). Importantly, aging is associated with a decreased number of osteoprogenitor cells, inhibited proliferation, decreased mineralizing capacity, and a shift of osteogenic differentiation toward adipogenesis in senescent mesenchymal stromal cells (MSCs) (5)(6)(7). ...
The progressive decline of bone mass and the deterioration of bone microarchitecture are hallmarks of the bone aging. The resulting increase in bone fragility is the leading cause of bone fractures, a major cause of disability. As the frontline pharmacological treatments for osteoporosis suffer from low patients’ adherence and occasional side effects, the importance of diet regimens for the prevention of excessive bone fragility has been increasingly recognized. Indeed, certain diet components have been already associated to a reduced fracture risk. Organosulfur compounds are a broad class of molecules containing sulfur. Among them, several molecules of potential therapeutic interest are found in edible plants belonging to the Allium and Brassica botanical genera. Polysulfides derived from Alliaceae and isothiocyanates derived from Brassicaceae hold remarkable nutraceutical potential as anti-inflammatory, antioxidants, vasorelaxant and hypolipemic. Some of these effects are linked to the ability to release the gasotrasmitter hydrogen sulfide (H2S). Recent preclinical studies have investigated the effect of organosulfur compounds in bone wasting and metabolic bone diseases, revealing a strong potential to preserve skeletal health by exerting cytoprotection and stimulating the bone forming activity by osteoblasts and attenuating bone resorption by osteoclasts. This review is intended for revising evidence from preclinical and epidemiological studies on the skeletal effects of organosulfur molecules of dietary origin, with emphasis on the direct regulation of bone cells by plant-derived polysulfides, glucosinolates and isothiocyanates. Moreover, we highlight the potential molecular mechanisms underlying the biological role of these compounds and revise the importance of the so-called ‘H2S-system’ on the regulation of bone homeostasis.
... The bone marrow mesenchymal stem cells (MSCs) are multipotent and capable of differentiating into several distinct cell lineages in vitro, including osteoblasts, adipocytes, chondrocytes, muscle cells, and even neuronal cells (21)(22)(23)(24). In bone tissues, MSCs give rise to osteoblasts or marrow adipocytes governed, in large part, by marrow microenvironment and developmental stages as these two pathways are reported to have a reciprocal relationship (25)(26)(27). In this study, we aimed to identify novel endogenous genes that are regulated by GR in MSCs by analyzing GR-deficient MSCs. ...
Glucocorticoids (GCs) are potent anti-inflammatory and immunosuppressive agents. However, their clinical usage is limited by severe multisystemic side effects. Glucocorticoid induced osteoporosis results in significant morbidity and mortality but the cellular and molecular mechanisms underlying GC-induced bone loss are not clear. GC use results in decreased osteoblast differentiation with increased marrow adiposity through effects on bone marrow stem cells. GC effects are transduced through its receptor (GR). To identify novel GR regulated genes, we performed RNA sequencing (RNA-Seq) analysis comparing conditional GR knockout mouse made by crossing the floxed GR animal with the Col I promoter-Cre, versus normal floxed GR without Cre, and that testing was specific for Col I promoter active cells, such as bone marrow mesenchymal stem/osteoprogenitor cells (MSCs) and osteoblasts. Results showed 15 upregulated genes (3- to 10-fold) and 70 downregulated genes (-2.7- to -10-fold), with the long noncoding RNA X-inactive specific transcript (Xist) downregulated the most. The differential expression of genes measured by RNA-Seq was validated by qRT-PCR analysis of selected genes and the GC/GR signaling-dependent expression of Xist was further demonstrated by GC (dexamethasone) treatment of GR-deficient MSCs in vitro and by GC injection of C57BL/6 mice (wild-type males and females) in vivo. Our data revealed that the long noncoding RNA Xist is a GR regulated gene and its expression is induced by GC both in vitro and in vivo. To our knowledge, this is the first evidence showing that Xist is transcriptionally regulated by GC/GR signaling.
... For example, hyperglycemia drives the accumulation of advanced glycation end products that impair bone formation and decrease bone strength by inducing excessive non-enzymatic cross-linking of the collagen matrix [3]. A strong correlation also exists between increased body fat mass and marrow adipose tissue (MAT) volume and bone loss in mouse models of DIO [4][5][6][7] due to the anti-osteogenic activity of secreted fatty acids, adipokines, and RANKL [8][9][10][11]. Excess body fat has also been linked to high serum leptin levels [12,13], and while effects of leptin on bone are complex [14,15], its overproduction is associated with a low bone mass phenotype [16]. Obesity-induced increases in serum leptin levels have also been shown to skew bifurcation of leptin receptor (LEPR) expressing skeletal stem/progenitor cells (SSPCs), which function as precursors of bone and fat in adult bone marrow [17], toward adipogenesis at the expense of osteogenesis [18]. ...
Obesity and type II diabetes mellitus (T2DM) are prominent risk factors for secondary osteoporosis due to the negative impacts of hyperglycemia and excessive body fat on bone metabolism. While the armamentarium of anti-diabetic drugs is expanding, their negative or unknown impacts on bone metabolism limits effectiveness. The inactivation of inositol hexakisphosphate kinase 1 (IP6K1) protects mice from high-fat-diet (HFD)-induced obesity (DIO) and insulin resistance by enhancing thermogenic energy expenditure, but the role of this kinase and the consequences of its inhibition on bone metabolism are unknown. To determine if IP6K1 inhibition in obese mice affords protection against obesity-induced metabolic derangements and bone loss, we maintained 2-month-old mice on a normal chow control diet or HFD under thermal neutral conditions for 100 d. Beginning on day 40, HFD-fed mice were divided into two groups and administered daily injections of vehicle or the pan-IP6K inhibitor TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl) purine]. HFD-fed mice developed obesity, hyperglycemia, hyperlipidemia, and secondary osteoporosis, while TNP administration protected mice against HFD-induced metabolic and lipid derangements and preserved bone mass, mineral density, and trabecular microarchitecture, which correlated with reduced serum leptin levels, reduced marrow adiposity, and preservation of marrow resident skeletal stem/progenitor cells (SSPCs). TNP also exhibited hypotensive activity, an unrealized benefit of the drug, and its prolonged administration had no adverse impacts on spermatogenesis. Together, these data indicate that the inhibition of IP6K1 using selective inhibitors, such as TNP, may provide an effective strategy to manage obesity and T2DM due to its bone sparing effects.
... They found that the cancellous bone volume was significantly reduced, and the fat content in bone marrow was notably increased in the elderly and patients with osteoporosis. By studying the pathological anatomy of iliac bone in 84 cadaver specimens, Meunier et al 16 observed that the content of adipose tissue decreased from about 60% of the elderly to about 15% of the young, and the content of cancellous bone was reduced from about 26% to about 16%. Naveiras et al 17 proved that bone-marrow adipocytes in the vertebral body were the main negative regulators of the bone marrow microenvironment. ...
Background
To assess whether the fat signal intensity and fat fraction (FF) of the lumbar vertebrae as measured on the Dixon chemical shift magnetic resonance imaging (MRI) technique can be correlated with the lumbar vertebra bone mineral density (BMD) measured using dual-energy X-ray absorptiometry (DXA).
Methods
Forty-five patients were retrospectively collected, and 180 lumbar vertebral bodies (L1-L4) were included. All patients underwent DXA and MRI examinations of the lumbar spine. Taking the T value of DXA as the gold standard and using the diagnostic criteria of the World Health Organization: T score ≥ −1.0SD as normal, −1.0 ~ −2.5SD as osteopenia, and ≤ −2.5SD as osteoporosis. Meanwhile, the signal intensity on T2WI was measured, and FF of L1-L4 vertebral bodies was calculated on MRI images. Bone marrow fat FF calculation formula: FF = [Mfat/(Mfat + Mwater)] × 100% (Mwater and Mfat refer to the total pixel signal intensity value of the region of interest in water image and lipid image, respectively). Finally, the association of signal intensity and FF with DXA was evaluated.
Results
Totally 180 vertebral bodies in 45 patients were enrolled. According to the T value, they were divided into the normal group (n = 70), osteopenia group (n = 40), and osteoporosis group (n = 70). The fat signal intensity of the normal group, osteopenia group, and osteoporosis group were 96.6 ± 21.8, 154.5 ± 48.7, 216.3 ± 92.6, and the FF were 30.1 ± 6.2%, 52.6 ± 7.6%, 77.5 ± 7.9%, respectively. Among the three groups, the lumbar T2 fat signal intensity and FF had statistical differences (P < 0.01). Besides, the lumbar fat signal intensity and FF were negatively related to DXA (r =−0.65 and −0.93, P < 0.01).
Conclusion
The fat content calculated using the Dixon chemical shift MRI had an inverse relation with BMD. Moreover, the Dixon chemical shift MRI might provide complementary information to osteoporosis-related research fields.
... Therefore, these patients are more likely to be treated with bisphosphonates which decrease bone resorption and consequentially increases bone quality [30]. Of note, bone marrow adipocytes found abundantly in bone marrow tissue account for 15 % of the bone marrow volume in young adults, increasing significantly to 60 % by the age of 65 years old, irrespective of BMI [31]. This might explain the less apparent effect of obesity on bone. ...
Background
Metastasis from breast cancer (BC) has a predilection for the skeleton. Due to its osteolytic nature, breast cancer bone metastasis (BCBM) appears to increase fracture risk. The association between obesity and its effect on bone seems to be skeletal site-specific. The incidence of pathological fractures often involves the axial skeleton even though the most debilitating effects of fractures are caused in the appendicular skeleton. Whether obesity increases fracture risk in BCBM remains inconclusive, however. At present, there is no literature that examines the effects of obesity on BCBM, and fracture risk are as such we sought to determine the effect of obesity on fracture risk in BC. This is the focus of the review.
Objectives
This scoping review aims to examine the link between fracture outcomes of women with BC and obesity as reported by Body Mass Index (BMI). The purpose of this study is to determine if current literature suggests obesity increases fracture risk in women with BC.
Design
We conducted a comprehensive literature search for breast cancer bone metastasis, obesity, and fracture risk in PubMed, Cochrane Library, NIH Clinical Trials, and OpenGrey. Articles that included BC, obesity, and fracture risk were included for analysis. Data were pooled, charted, analysed, and reported according to PRISMA-ScR standards.
Data synthesis and Results
Each outcome was stratified by BMI (obese or non-obese) status in women with breast cancer. Five studies were eligible for analysis and relevant data was charted to allow results to be synthesised. We found four out of five studies reported a positive association between BMI and fracture risk in females with breast cancer.
Conclusions
We found a potential association of obesity and fracture risk in breast cancer. However, as we conducted this study it was evident that there is limited literature available on this topic and none for breast cancer bone metastasis. This poses an important direction for future research. Larger and robust pre-clinical and clinical randomized control trials are needed to better understand the relation between obesity and metastatic breast cancer.
OBJECTIVE
Low bone mineral density (BMD) significantly increases the risk of complications in patients undergoing spinal fusion. Existing evidence indicates that traditional dual-energy x-ray absorptiometry (DEXA) and quantitative CT (QCT) screening are underutilized in spine surgery. The MRI-based vertebral bone quality (VBQ) score provides a tool for primary screening of bone density. The validity of this score as a predictor across sexes has not been investigated. This study aimed to explore the effect of sex on the diagnostic efficacy of the VBQ in predicting osteopenia/osteoporosis and whether a sex-specific threshold exists.
METHODS
In this retrospective cohort study, patients who underwent lumbar fusion at a tertiary care center were reviewed. VBQ was obtained by noncontrast T1-weighted MRI. Patients were stratified according to sex and bone density. Data were analyzed between the groups. Pearson correlation analysis and linear regression were used to analyze the correlation between the VBQ and DEXA T values. Receiver operating characteristic (ROC) curve analysis, including area under the curve (AUC) calculation, was used to evaluate the predictive performance of VBQ for low BMD in both sexes.
RESULTS
A total of 271 patients (92 male, 179 female patients) were analyzed. The correlation coefficient between VBQ and the lowest T value was −0.40 for male and −0.554 for female patients. In comparing the bone density subgroups, among male patients a significant difference in the VBQ scores was observed only between the normal and osteoporosis subgroups (p = 0.012). VBQ demonstrated statistically significant differences among female patients across all three subgroups (p < 0.001). The ROC analysis revealed that the predictive performance of VBQ in detecting low BMD was more consistent with the gold-standard DEXA results in female than in male patients (AUC 0.647 vs AUC 0.823, p = 0.02). The optimal thresholds were similar in both sexes.
CONCLUSIONS
Compared with male patients, VBQ has better discrimination between female patients with low BMD and those with normal bone density. Although the correlation between VBQ and bone density is weaker in male than in female patients, the optimal thresholds are similar in both sexes.
This study investigates the effects of peroxisome proliferator-activated receptor gamma (PPARγ) inhibition on bone and immune cell profile in aged female mice, as well as in vitro stromal stem cell (SSC) osteogenic differentiation and inflammation gene expression. The hypothesis was that inhibition of PPARγwould increase bone mass and alter immune and other cellular functions. Our results showed that treatment with PPARγantagonist GW9662 for six weeks reduced bone volume and trabecular number and increased trabecular spacing. However, inhibition of PPARγhad no significant effect on marrow and spleen immune cell composition in aged female mice. In vitro experiments indicated that GW9662 treatment increased the expression of osteogenic genes but did not affect adipogenic genes. Additionally, GW9662 treatment decreased the expression of several inflammation related genes. Overall, these findings suggest that PPARγinhibition may have adverse effects on bone in aged female mice.
Objective:
Osteoporosis is the most common skeletal disease in humans. Early onset of osteoporosis is usually asymptomatic, so early diagnosis is critical. The purpose of this study was to analyze the value of MRI-based VBQ scores for evaluating osteoporosis.
Methods:
We searched PubMed, Embase, the Cochrane Library databases, Web of Science, and some Chinese electronic databases for published articles and the ClinicalTrials.gov site for completed but unpublished studies on evaluating the value of MRI-based VBQ scores for evaluating osteoporosis. We calculated the summarized sensitivity, specificity, the ROC curve (AUC) values and their 95% confidence intervals (CIs) using MetaDiSc 1.4 software and STATA.
Results:
Our study included 8 studies involving 999 patients of which 660 patients were diagnosed with osteopenia/osteoporosis, and 339 patients were identified as having normal BMD. The pooled sensitivity was 0.809 (95% CI, 0.777-0.838, I2 = 78.8%), the pooled specificity was 0.640 (95% CI, 0.587-0.691, I2 = 85.9%), and the pooled AUC was 0.8375.
Conclusion:
MRI-based VBQ scores provided high sensitivity and moderate specificity in detecting osteoporosis. Opportunistic use of VBQ scores could be considered, e.g. before lumbar spine surgery.
Prospero registration number:
CRD42022377024.
Adipose tissue is a dynamic component of the bone marrow, regulating skeletal remodelling and secreting paracrine and endocrine factors that can affect haematopoiesis, as well as potentially nourishing the bone marrow during periods of stress. Bone marrow adipose tissue is regulated by multiple factors, but particularly nutrient status. In this Review, we examine how bone marrow adipocytes originate, their function in normal and pathological states and how bone marrow adipose tissue modulates whole-body homoeostasis through actions on bone cells, haematopoietic stem cells and extra-medullary adipocytes during nutritional challenges. We focus on both rodent models and human studies to help understand the unique marrow adipocyte, its response to the external nutrient environment and its effects on the skeleton. We finish by addressing some critical questions that to date remain unanswered.
Unlabelled:
A simple index calculated by dividing the greater trochanter signal intensity by that of the femoral neck on coronal T1-weighted magnetic resonance images of the hip may be useful as an opportunistic screening tool to differentiate normal vs. abnormal bone mineral density.
Purpose:
The aim of this study is to evaluate the efficacy of the greater trochanter/femoral neck (T/N) signal intensity (SI) ratio on T1 weighted images of the hip in differentiating patients with normal vs. abnormal bone mineral density (BMD) using hip dual-energy x-ray absorptiometry (DXA) as the reference.
Methods:
Three BMD groups according to the T score of the femoral neck (i.e., normal, osteopenia, and osteoporosis) were created, and 20 patients were included for each group. The T/N ratio was calculated by dividing the greater trochanter SI by that of the femoral neck on coronal T1-weighted images. Receiver-operator characteristic (ROC) analysis was performed to determine diagnostic efficacy.
Results:
The mean age was 59.2±9.4; there were 57 women and 3 men. The mean BMD was 0.67±0.14 g/cm2. The mean T/N ratio for the normal, osteopenia, and osteoporosis groups were 1.37 (±0.12), 1.19 (±0.10), and 1.18 (±0.13), respectively. When the osteopenia and osteoporosis groups were combined into one group, i.e., low BMD group, the mean T/N ratio was 1.18 (±0.11), and it was significantly different from that of the normal BMD group (p<0.00001). In ROC analysis, the area under curve (AUC) for the T/N ratio in the diagnosis of low BMD was 0.870. An optimal cutoff value of 1.28 was found for the differentiation of normal vs. abnormal BMD with 80% sensitivity and 80% specificity.
Conclusions:
The T/N ratio seems to be effective at differentiating patients with normal vs. abnormal BMD and may help triage patients for additional evaluation.
Understanding the axis of the human microbiome and physiological homeostasis is an essential task in managing deep-space-travel-associated health risks. The NASA-led Rodent Research 5 mission enabled an ancillary investigation of the gut microbiome, varying exposure to microgravity (flight) relative to ground controls in the context of previously shown bone mineral density (BMD) loss that was observed in these flight groups. We demonstrate elevated abundance of Lactobacillus murinus and Dorea sp. during microgravity exposure relative to ground control through whole-genome sequencing and 16S rRNA analyses. Specific functionally assigned gene clusters of L. murinus and Dorea sp. capable of producing metabolites, lactic acid, leucine/isoleucine, and glutathione are enriched. These metabolites are elevated in the microgravity-exposed host serum as shown by liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolomic analysis. Along with BMD loss, ELISA reveals increases in osteocalcin and reductions in tartrate-resistant acid phosphatase 5b signifying additional loss of bone homeostasis in flight.
Abstract Background Current evidence suggests that the magnetic resonance imaging (MRI)-based vertebral bone quality (VBQ) score is a good parameter for evaluating bone quality. We aimed to assess whether the VBQ score can predict the occurrence of postoperative cage subsidence after oblique lumbar interbody fusion (OLIF) surgery. Methods Patients (n = 102) who had undergone single-level OLIF with a minimal follow-up for 1 year were reviewed in this study. Demographic and radiographic data of these patients were collected. Cage subsidence was defined as ≥ 2 mm of cage migration into the inferior endplate, superior endplate, or both. Further, the MRI-based VBQ score was measured on T1-weighted images. Moreover, univariable and multivariable binary logistic regression analyses were performed. Meanwhile, Pearson analysis was used to evaluate the correlation among the VBQ score, average lumbar dual-energy X-ray absorptiometry (DEXA) T-score, and degree of cage subsidence. Furthermore, ad-hoc analysis was used along with receiver operating characteristic curve analysis to assess the predictive ability of the VBQ score and average lumbar DEXA T-score. Results Of 102 participants, cage subsidence was observed in 39 (38.24%) patients. According to the univariable analysis, patients with subsidence had older age, higher antiosteoporotic drug use, larger disk height change, a more concave morphology of inferior and superior endplates, higher VBQ score, and lower average lumbar DEXA T-score compared to patients without subsidence. In the multivariable logistic regression analysis, a higher VBQ score was significantly associated with an increased risk of subsidence (OR = 23.158 ± 0.849, 95% CI 4.381–122.399, p
Background Knowledge about regulating transcription factors (TFs) for osteoblastogenesis from mesenchymal stem cells (MSCs) is limited. Therefore, we investigated the relationship between genomic regions subject to DNA‐methyla‐ tion changes during osteoblastogenesis and the TFs known to directly interact with these regulatory regions.
Results The genome‐wide DNA‐methylation signature of MSCs differentiated to osteoblasts and adipocytes was determined using the Illumina HumanMethylation450 BeadChip array. During adipogenesis no CpGs passed our test for significant methylation changes. Oppositely, during osteoblastogenesis we identified 2462 differently significantly methylated CpGs (adj. p < 0.05). These resided outside of CpGs islands and were significantly enriched in enhancer regions. We confirmed the correlation between DNA‐methylation and gene expression. Accordingly, we developed a bioinformatic tool to analyse differentially methylated regions and the TFs interacting with them. By overlaying our osteoblastogenesis differentially methylated regions with ENCODE TF ChIP‐seq data we obtained a set of candidate TFs associated to DNA‐methylation changes. Among them, ZEB1 TF was highly related with DNA‐methylation. Using RNA interference, we confirmed that ZEB1, and ZEB2, played a key role in adipogenesis and osteoblastogenesis pro‐ cesses. For clinical relevance, ZEB1 mRNA expression in human bone samples was evaluated. This expression posi‐ tively correlated with weight, body mass index, and PPARγ expression.
Conclusions In this work we describe an osteoblastogenesis‐associated DNA‐methylation profile and, using these data, validate a novel computational tool to identify key TFs associated to age‐related disease processes. By means of this tool we identified and confirmed ZEB TFs as mediators involved in the MSCs differentiation to osteoblasts and adipocytes, and obesity‐related bone adiposity.
The differentiation of adipocytic and osteogenic cells has been investigated in cultures of adult rat marrow stromal cells. Adipocytic differentiation was assessed using morphological criteria, changes in expression of procollagen mRNAs, consistent with a switch from the synthesis of predominantly fibrillar (types I and III) to basement membrane (type IV) collagen, and the induction of expression of aP2, a specific marker for differentiation of adipocytes. Osteogenic differentiation was assessed on the basis of changes in the abundance of the mRNAs for the bone/liver/kidney isozyme of alkaline phosphatase and the induction of mRNAs for bone sialoprotein and osteocalcin. In the presence of foetal calf serum and dexamethasone (10(−8) M) there was always differentiation of both adipocytic and osteogenic cells. When the steroid was present throughout primary and secondary culture the differentiation of osteogenic cells predominated. Conversely, when dexamethasone was present in secondary culture only, the differentiation of adipocytes predominated. When marrow stromal cells were cultured in the presence of dexamethasone in primary culture and dexamethasone and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3; 10(−8) M) in secondary culture, the differentiation of adipocytes was inhibited whereas the differentiation of osteogenic cells was enhanced, as assessed by an increase in expression of osteocalcin mRNA. The results, therefore, demonstrate an inverse relationship between the differentiation of adipocytic and osteogenic cells in this culture system and are consistent with the possibility that the regulation of adipogenesis and osteogenesis can occur at the level of a common precursor in vivo.
Changes in bone architecture and metabolism with aging increase the likelihood of osteoporosis and fracture. Age-onset osteoporosis is multifactorial, with contributory extrinsic and intrinsic factors including certain medical problems, specific prescription drugs, estrogen loss, secondary hyperparathyroidism, microenvironmental and cellular alterations in bone tissue, and mechanical unloading or immobilization. At the histological level, there are changes in trabecular and cortical bone as well as marrow cellularity, lineage switching of mesenchymal stem cells to an adipogenic fate, inadequate transduction of signals during skeletal loading, and predisposition toward senescent cell accumulation with production of a senescence-associated secretory phenotype. Cumulatively, these changes result in bone remodeling abnormalities that over time cause net bone loss typically seen in older adults. Age-related osteoporosis is a geriatric syndrome due to the multiple etiologies that converge upon the skeleton to produce the ultimate phenotypic changes that manifest as bone fragility. Bone tissue is dynamic but with tendencies toward poor osteoblastic bone formation and relative osteoclastic bone resorption with aging. Interactions with other aging physiologic systems, such as muscle, may also confer detrimental effects on the aging skeleton. Conversely, individuals who maintain their BMD experience a lower risk of fractures, disability, and mortality, suggesting that this phenotype may be a marker of successful aging. © 2023 American Physiological Society. Compr Physiol 13:4355-4386, 2023.
BACKGROUND:
Surgeons can preoperatively assess bone quality using dual-energy X-ray absorptiometry or computed tomography; however, this is not feasible for all patients. Recently, a MRI-based scoring system was used to evaluate the lumbar spine's vertebral bone quality.
OBJECTIVE:
To create a similar MRI-based scoring system for the cervical spine (C-VBQ), correlate C-VBQ scores with computed tomography-Hounsfield units (HU), and evaluate the utility of this scoring system to independently predict cage subsidence after single-level anterior cervical diskectomy and fusion (ACDF).
METHODS:
Demographic, procedure-related, and radiographic data were collected for patients. Pearson correlation test was used to determine the correlation between C-VBQ and HU. Cage subsidence was defined as ≥3 mm loss of fusion segmental height. A multivariate logistic regression model was built to determine the correlation between potential risk factors for subsidence.
RESULTS:
Of 59 patients who underwent single-level ACDF, subsidence was found in 17 (28.8%). Mean C-VBQ scores were 2.22 ± 0.36 for no subsidence levels and 2.83 ± 0.38 (P < .001) for subsidence levels. On multivariate analysis, a higher C-VBQ score was significantly associated with subsidence (odds ratio = 1.85, 95% CI = 1.39-2.46, P < .001) and was the only significant independent predictor of subsidence after ACDF. There was a significant negative correlation between HU and C-VBQ (r2 = −0.49, P < .001).
CONCLUSION:
We found that a higher C-VBQ score was significantly associated with cage subsidence after ACDF. Furthermore, there was a significant negative correlation between C-VBQ and HU. The C-VBQ score may be a valuable tool for assessing preoperative bone quality and independently predicting cage subsidence after ACDF.
Postmenopausal osteoporosis (PMOP) is a common bone disease characterized by decreased bone density and increased bone fragility due to decreased estrogen levels. Qiangguyin (QGY) is transformed from the famous traditional Chinese medicine BuShen Invigorating Blood Decoction. In this study, we used QGY to treat PMOP. We observed that QGY significantly reduced fat accumulation in the chondro-osseous junction. However, its specific mechanism of action remains unclear. To determine the specific molecular mechanism of QGY, we explored the pharmacological mechanism by which QGY reduces fat accumulation in the chondro-osseous junction through network pharmacological analysis. The active components and targets related to PMOP and QGY were screened from different databases, forming a composition-target-disease network. Next, a comprehensive analysis platform including protein-protein interaction (PPI) network, Gene Ontology (GO) enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were established. The results revealed that QGY inhibits adipogenic differentiation by activating the mitogen-activated protein kinase (MAPK) signaling pathway, thus reducing the accumulation of fat in the chondro-osseous junction. For further verification. In vitro and in vivo experiments were carried out. Our data showed that QGY significantly reversed the high expression of fatty acid binding protein 4 (FABP4) and peroxisome proliferator-activated receptor γ (PPARγ). Further, QGY prevents fat accumulation by inhibiting the expression of p38. In summary, the results of this study suggested that QGY-induced phenotypic changes are related to the activation of the p38 MAPK signaling pathway.
A growing number of studies reported that obesity is one of the major inducements for osteoporosis by promoting excessive adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Marine-derived DHA-enriched phosphatidylcholine (DHA-PC) exhibited activities to improve ovariectomized-induced osteoporosis and kidney damage. However, the potential effect of DHA-PC and efficacy differences between DHA-PC and traditional DHA (DHA-triglyceride, DHA-TG) on BMSCs differentiation in obesity-induced osteoporosis were not clear. In the present study, obesity-induced osteoporotic mice were supplemented with DHA-TG and DHA-PC for 120 days. Results showed that supplementing with DHA-PC improved the bone mineral density and biomechanical properties, increased the new bone formation rate by 55.2%, and reduced the amount of bone marrow fat to a greater extent than DHA-TG. Further in vitro results showed that DHA-PC significantly promoted the osteogenic differentiation and inhibited the adipogenic differentiation of BMSCs. Mechanistically, DHA-PC supplement up-regulated Wnt/β-catenin pathway in BMSCs and up-regulated the expression of osteogenic transcription factors, thereby promoting osteogenic differentiation. In summary, DHA-PC exerted a superior effect to DHA-TG in improving obesity-induced osteoporosis. The results provided new evidence for the application of different molecular forms of DHA in treatment of osteoporosis.
Background
Clinical Orthopaedics and Related Research is one of the most influential and reputable scientific journals in the field of orthopaedics. Some of the most reputable publications related to orthopaedic research can be attributed to this journal and it continues to have a significant impact on modern research.
Objective
The purpose of this study is to identify the most influential articles, in terms of number of citations, published by Clinical Orthopaedics and Related Research. The goal of analyzing the most cited articles in is to create a baseline for future researchers to build upon and to uncover any trends in orthopaedic research.
Methods
Preferred Reporting Items for Systematic Reviews guidelines were used to structure the data collection and analysis of this study. The Scopus database was used to compile the publication data. Data was then exported to an excel sheet to be further analyzed via a multi-author review process.
Results
The most cited article was “A Clinical Method of Functional Assessment of the Shoulder” by Constant et al.. The 50 articles analyzed in this study were cited a total of 32,404 times, averaging 719 citations per year, per publication. The oldest article was published in 1971, and the newest in 2008. The United States was the country with the most attributable publications and The University of Florida was the most contributory institution.
Conclusions
Our study recognizes Clinical Orthopaedics and Related research as having a strong predilection for older articles and a continued strength for modern publications.
BACKGROUND CONTEXT
Cage subsidence following transforaminal lumbar interbody fusion (TLIF) has been associated with poor bone quality. Current evidence suggests that the magnetic resonance imaging (MRI)-based vertebral bone quality (VBQ) score correlates with poor bone quality.
PURPOSE
To our knowledge, this is the first study to assess whether the VBQ score can predict the occurrence of postoperative cage subsidence after TLIF surgery.
DESIGN/SETTING
Retrospective single-center cohort.
PATIENT SAMPLE
Patients undergoing single-level TLIF for degenerative spine disease between February 2014 and October 2021.
OUTCOME MEASURES
Extent of subsidence.
METHODS
Demographic, procedure-related, and radiographic data were collected for study patients. VBQ scores were determined from preoperative T1-weighted MRI. Subsidence was defined as ≥2mm of migration of the cage into the superior or inferior endplate or both. Univariate and multivariate logistic regression were used to determine the correlation between potential risk factors for subsidence and actual subsidence rates.
RESULTS
Subsidence was observed among 42 of the 74 study patients. The mean VBQ scores were 2.9±0.5 for patients with subsidence and 2.5±0.5 for patients without subsidence. The difference among groups was significant (p=0.003). On multivariate logistic regression, a higher VBQ score was significantly associated with an increased risk of subsidence (OR=1.5, 95% CI=1.160-1.973, p=.004) and was the only significant independent predictor of subsidence after TLIF.
CONCLUSION
We found that a higher VBQ score was significantly associated with cage subsidence following TLIF. The MRI-VBQ score may be a valuable tool for assisting in identifying patients at risk of cage subsidence following TLIF.
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