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Endochondral ossification (EO), by which long bones of the axial skeleton form, is a tightly regulated process involving chondrocyte maturation with successive stages of proliferation, maturation, and hypertrophy, accompanied by cartilage matrix synthesis, calcification, and angiogenesis, followed by osteoblast-mediated ossification. This developme...
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A new mathematical model is presented to study the regulatory effect of the growth factors during the bone fracture healing process. It consists of a system of nonlinear ordinary differential equations that represents the interactions among macrophages, mesenchymal stem cells, osteoblasts, cytokines, and growth factors. A qualitative analysis of th...
Background:
The healing of a bone injury is a highly complex process involving a multitude of different tissue and cell types, including immune cells, which play a major role in the initiation and progression of bone regeneration.
Methods:
We histologically analyzed the spatio-temporal occurrence of cells of the innate immune system (macrophages...
Background: Fracture nonunion is a common and challenging complication. Studies have reported that direct current stimulation can promote fracture healing, but there are reports that there are differences in cell density near positive and negative electrodes during direct current stimulation. The purpose of this study is to explore the effect of di...
Citations
... For decades, the idea has been that the source of osteoprogenitor cells to replace the cartilage mold is the perichondrium/periosteum and the abluminal side of blood vessels invading the cartilage matrix during endochondral ossification [149][150][151]. Recent studies corroborate the early evidence of multiple cellular fates of hypertrophic chondrocytes, such as apoptosis or transdifferentiation into osteoblasts [148,[152][153][154]. Peptides from sea cucumber intestine promote chondrocyte-toosteoblast transdifferentiation in vitro and in vivo through integrin-mediated Wnt signaling, increasing growth plate height, Col X expression, and osteogenesis, suggesting a potential role in treating bone diseases [155]. ...
... Endochondral ossification. Adapted from Ref.[148]. Created with BioRender.com. ...
... Chondrocytes in the fracture gap are different than those in the articular cartilage that line the ends of bone within the joint in that these chondrocytes undergo hypertrophic maturation to promote mineralization of the cartilage matrix. Hypertrophic chondrocytes also stimulate vascularization and innervation of the cartilage matrix, which initiates formation of trabecular bone through transformation of chondrocytes into osteoblasts [19]. Lastly, the newly formed trabecular bone remodels into cortical bone resembling that of the original long bone [20]. ...
There is an unmet need for improved, clinically relevant methods to longitudinally quantify bone healing during fracture care. Here we develop a smart bone plate to wirelessly monitor healing utilizing electrical impedance spectroscopy (EIS) to provide real-time data on tissue composition within the fracture callus. To validate our technology, we created a 1-mm rabbit tibial defect and fixed the bone with a standard veterinary plate modified with a custom-designed housing that included two impedance sensors capable of wireless transmission. Impedance magnitude and phase measurements were transmitted every 48 h for up to 10 weeks. Bone healing was assessed by X-ray, µCT, and histology. Our results indicated the sensors successfully incorporated into the fracture callus and did not impede repair. Electrical impedance, resistance, and reactance increased steadily from weeks 3 to 7—corresponding to the transition from hematoma to cartilage to bone within the fracture gap—then plateaued as the bone began to consolidate. These three electrical readings significantly correlated with traditional measurements of bone healing and successfully distinguished between union and not-healed fractures, with the strongest relationship found with impedance magnitude. These results suggest that our EIS smart bone plate can provide continuous and highly sensitive quantitative tissue measurements throughout the course of fracture healing to better guide personalized clinical care.
... In the subchondral bone of osteoarthritis, the capillaries are stimulated by abnormal mechanical stress, and the molecular balance between promoting and inhibiting angiogenesis is broken, tending to promote angiogenesis molecules. This pathologic change of angiogenesis can stimulate the surrounding cells to express a variety of angiogenic factors, including VEGFA, platelet-derived growth factors (PDGFs), hemo-lytic phosphate (LPA), and angiopoietins (Angs) [19]. VEGF and Angs can activate matrix degrading enzymes, including plasminogen activators (PAs) and matrix metalloproteinases (MMPs), to relax the matrix and allow endothelial cells to migrate and germinate. ...
Purpose:
The effect of resveratrol on subchondral bone in osteoarthritis was explored by constructing a mouse model of osteoarthritis and giving resveratrol as intervention.
Methods:
The degree of proteoglycan loss in articular cartilage was assessed by safranine fast green staining. The expressions of Lubricin and Aggrecan, COLX, and MMP-13, the co-expression of CD31 and Endomucin, and the expression of angiogenesis-related factors were determined by immunohistochemistry. TRAP stain and immunostaining were used to assess abnormal subchondral bone resorption and bone formation. Angiography was employed to analyze the effect of resveratrol on the proliferation of subchondral bone vessels.
Results:
Resveratrol inhibited cartilage thickening and the increase of COLX and MMP-13 expression, delayed the loss of proteoglycan, Lubricin, and Aggrecan, and inhibited osteoclast differentiation by up-regulating osteoprotegerin (OPG) and down-regulating the expression of RANKL. Angiography showed that resveratrol can reduce the abnormally elevated number and volume of blood vessels in the subchondral bone. Immunostaining showed that resveratrol inhibited CD31hiEmcnhi angiogenesis and high expression of VEGFA and Angiopoietin-1.
Conclusion:
Resveratrol inhibits osteoclast differentiation and reduces active bone resorption by regulating the OPG/RANKL/RANK pathway, and inhibits the abnormal proliferation of CD31hiEmcnhi blood vessels by downregulating the expression of VEGFA and Angiopoiein-1, thereby eliminating the pathologic coupling mechanism of osteogenesis and vascularization, and delaying the progression of osteoarthritis.
... Unlike direct intramembranous ossification, endochondral ossification involves transitioning from a cartilaginous tissue template to mineralized bone. The reformation of cartilaginous tissues into osseous tissue encompasses chondrocyte induced vascularization of the cartilage, recruitment of osteoprogenitors, chondrocyte apoptosis or transdifferentiation, and ECM transformation by osteoclasts and osteoblasts (Javaheri et al., 2018;Mackie et al., 2011). All of which is coordinated through systemic hormone signaling (e.g., growth hormone and thyroid hormone) and local growth factor signaling (e.g., VEGF and FGF) between and within several cell populations (Mackie et al., 2011;Provot and Schipani, 2005). ...
Tissue remodeling is broadly defined as the reorganization or restoration of existing tissues. Tissue remodeling processes are responsible for directing the development and maintenance of tissues, organs, and overall morphology of an organism. Therefore, studying the regulatory and mechanistic aspects of tissue remodeling allows one to decipher how tissue structure and function is manipulated in animals. As such, research focused on investigating natural tissue reorganization in animal model organisms has great potential for advancing medical therapies, in conjunction with tissue engineering and regenerative medicine. Here we discuss the molecular and cellular mechanisms responsible for tissue remodeling events that occur across several animal phyla. Notably, this review emphasizes the molecular and cellular mechanisms involved in embryonic and postnatal physiological tissue remodeling events, ranging from metamorphosis to bone remodeling during functional adaptation.
... Furthermore, our findings indicate that the characteristic subchondral bone sclerosis observed in the medial site of epiphysis (19,38) was also significantly reduced in response to [-1A] TIMP-3 overexpression. This suggests that [-1A]TIMP-3 may regulate communication between chondrocytes and bone cells, or may indeed have a direct effect on bone through chondrocyte transdifferentiation into osteoblasts (39). Alternatively, we need to explore the possibility that the primary effect of [-1A]TIMP-3 could be the reduction in subchondral bone sclerosis, which in turn improves cartilage stability. ...
Objective
Cartilage destruction in osteoarthritis (OA) is mediated mainly by matrix metalloproteinases (MMPs) and ADAMTS. The therapeutic candidature of targeting aggrecanases has not yet been defined in joints in which spontaneous OA arises from genetic susceptibility, as in the case of the STR/Ort mouse, without a traumatic or load‐induced etiology. In addition, we do not know the long‐term effect of aggrecanase inhibition on bone. We undertook this study to assess the potential aggrecanase selectivity of a variant of tissue inhibitor of metalloproteinases 3 (TIMP‐3), called [‐1A]TIMP‐3, on spontaneous OA development and bone formation in STR/Ort mice.
Methods
Using the background of STR/Ort mice, which develop spontaneous OA, we generated transgenic mice that overexpress [‐1A]TIMP‐3, either ubiquitously or conditionally in chondrocytes. [‐1A]TIMP‐3 has an extra alanine at the N‐terminus that selectively inhibits ADAMTS but not MMPs. We analyzed a range of OA‐related measures in all mice at age 40 weeks.
Results
Mice expressing high levels of [‐1A]TIMP‐3 were protected against development of OA, while those expressing low levels were not. Interestingly, we also found that high levels of [‐1A]TIMP‐3 transgene overexpression resulted in increased bone mass, particularly in females. This regulation of bone mass was at least partly direct, as adult mouse primary osteoblasts infected with [‐1A]TIMP‐3 in vitro showed elevated rates of mineralization.
Conclusion
The results provide evidence that [‐1A]TIMP‐3–mediated inhibition of aggrecanases can protect against cartilage degradation in a naturally occurring mouse model of OA, and they highlight a novel role that aggrecanase inhibition may play in increased bone mass.
... Histologically, the secondary cartilage differs to the primary cartilage in its surface layer, that is, the perichondrium undifferentiated pre-chondroblastic cells that secrete a collagen I rich matrix, different to the collagen II matrix secreted by chondrocytes [16,17]. This is the kind of undifferentiated cells that proliferate and mature to produce CMC growth, instead of the deep layer chondrocytes in the primary cartilage, derived from the embryonal cartilaginous primordium, more genetically determined [16,18,19]. Therefore, the secondary cartilage is able to suffer phenotypic modifications responding to mechanic or functional loads that causes remodeling by an increment in the number of mesenchymal cells or, on the other hand, in absence of function causing a progressive reduction in the hypertrophic layer, reduction of the proteoglycan contents in the matrix, reduction of cartilage thickness and eventually, transformation of the CMC into bone tissue [20,21]. ...
... Later on, during the 9th week endochondral ossification takes place, involving the condylar blastema by cartilaginous tissue (soft condyle), due to migration and differentiation of mesenchymal cells to chondrocytes that secrete the extracellular matrix of cartilage rich in collagen type II [18]. ...
... The CMC is not determined by primary influences and is not covered by a cartilaginous matrix that isolates or protects it from local or external factors [18,19]. Therefore, its phenotype is able to change by mechanic or functional factors. ...
Abstract
Objective: To describe the early treatment of two patients with unilateral condylar hyperplasia (UCH) diagnosis and therapeutic sur- gical protocol (early condylectomy) supported by the current biological knowledge about the development and repair of mandibular condyle cartilage (MCC).
Methods: Review of the literature and two case description of the treatment. The two patients were girls, 12 and 13 year old. The follow up period was of 3 years. SPECT diagnostic, radiographic, photographic and tomographic images are presented.
Results: The literature summarized provides biological basis favoring the early treatment of UCH. The two cases were treated with the same surgical protocol obtaining good esthetic and functional stable results.
Discussion: The present literature review and clinical results provide biological basis to justify the practice of early condylectomy. Early intervention appears to be able to produce a successful outcome in terms of esthetic facial symmetry, avoiding dentoalveolar orthodontic compensations or additional orthognathic surgeries.
Keywords: Condylectomy; Facial Asymmetry; Orthodontics; Unilateral Condylar Hyperplasia
... However, recent studies demonstrated that hypertrophic chondrocytes are able to trans-differentiate into osteoblast-like cells and due to increased VEGF and RUNX2 expression in OA articular cartilage becomes vascularized and finally mineralized. This results in thickened tidemark and osteophyte formation [72,73]. The induction of further inflammatory mediators including IL-6, TNF, LIF, PGE2, NO, COX2 or iNOS by IL-1β induces in chondrocytes most of the catabolic processes described above and contributes in addition to synovial inflammation perpetuating cartilage tissue degradation by activating synovial fibroblasts and immune cells. ...
Osteoarthritis (OA) can be regarded as a chronic, painful and degenerative disease that affects all tissues of a joint and one of the major endpoints being loss of articular cartilage. In most cases, OA is associated with a variable degree of synovial inflammation. A variety of different cell types including chondrocytes, synovial fibroblasts, adipocytes, osteoblasts and osteoclasts as well as stem and immune cells are involved in catabolic and inflammatory processes but also in attempts to counteract the cartilage loss. At the molecular level, these changes are regulated by a complex network of proteolytic enzymes, chemokines and cytokines (for review: [1]). Here, interleukin-1 signaling (IL-1) plays a central role and its effects on the different cell types involved in OA are discussed in this review with a special focus on the chondrocyte.
... Can hypertrophic chondrocytes become osteoblasts and contribute to the osteogenic lineage? This question, which has been asked more than a century [32], has recently been readdressed to yield new answers. The process of endochondral ossification is predominantly understood in the context of its function in long bone development. ...
... Despite a lack of clarity regarding the function of Oct4A, it appears that chondrocytes may dedifferentiate, in a manner akin to that described for induced pluripotent cells, to regain progenitor capabilities that is consistent with the mechanism described by Song and Tuan [36]. Elucidation of the cellular reprogramming required to direct transition from cartilage to bone is a key target; however, the substantial overlap that exists between markers of hypertrophic chondrocytes and osteoblasts represent a significant hurdle in achieving this aim [32]. These difficulties in discerning the cellular reprogramming mechanisms are not altogether surprising, however, since chondrocytes and osteoblasts are known to share common osteochondroprogenitor origins during limb development. ...
Mechanics generated by muscle contraction act on skeletal elements during adult life as well as in the embryo and when disease processes are at play. This chapter will introduce a historical perspective to contextualize the emergence of these locomotor mechanics as a driver of change in the developing embryo skeleton. It will then explore relationships between the response of the emerging embryo skeleton and forces that have their origins in contracting musculature with those cell-derived forces with intracellular or cell–extracellular matrix interface origins. This will lead us to examine new perspectives concerning the emergence of a chondro-osseous cellular continuum. We will then focus on the role of mechanics in normal development, concentrating on joint development and endochondral ossification, as examples, to discuss whether there are distinct and critical mechanosensitive phases of skeletal development and, to provide an opportunity to pinpoint key pathways that are emerging as crucial in the embryonic acquisition of such skeletal mechanosensitivity. We will finish by contextualizing the function of these pathways in disease by reinforcing the idea that osteoarthritis hallmarks, which are shared with those driven by movement in the embryonic skeleton, might indeed also rely on locomotor mechanics.
Hypertrophic chondrocytes are found at unique locations at the junction of skeletal tissues, cartilage growth plate, articular cartilage, enthesis and intervertebral discs. Their role in the skeleton is best understood in the process of endochondral ossification in development and bone fracture healing. Chondrocyte hypertrophy occurs in degenerative conditions such as osteoarthritis. Thus, the role of hypertrophic chondrocytes in skeletal biology and pathology is context dependent. This review will focus on hypertrophic chondrocytes in endochondral ossification, in which they exist in a transient state, but acting as a central regulator of differentiation, mineralization, vascularization and conversion to bone. The amazing journey of a chondrocyte from being entrapped in the extracellular matrix environment to becoming proliferative then hypertrophic will be discussed. Recent studies on the dynamic changes and plasticity of hypertrophic chondrocytes have provided new insights into how we view these cells, not as terminally differentiated but as cells that can dedifferentiate to more progenitor-like cells in a transition to osteoblasts and adipocytes, as well as a source of skeletal stem and progenitor cells residing in the bone marrow. This will provide a foundation for studies of hypertrophic chondrocytes at other skeletal sites in development, tissue maintenance, pathology and therapy.
