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Expression of OB differentiation markers, transcription factors, RANKL and OPG in BMSCs co-cultured with H929. Co-cultures were performed with BMSCs and H929 (+) in the absence (−) or in the presence of 50 or 500 ng/ml anti-sclerostin mAb. H929 inhibited the expression of protein levels of COLL I (Aa), BSP II (Ab) and mRNA levels of OSTC (Ac) in BMSCs. The inhibition was partially rescued by the mAb. H929 also inhibited Fra-1 (Bd), Fra-2 (Be) and JunD (Bf) expression at protein level and the partial abrogation of these effects was observed in the presence of mAb. Moreover, the presence of H929 increased RANKL (Cg) and decreased OPG (Ch) expression. These effects were partially rescued by the presence of the mAb, as showed by histograms reporting the intensity of the bands quantified by densitometry and normalized to β-Actin.
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Wingless-type (Wnt) signaling through the secretion of Wnt inhibitors Dickkopf1, soluble frizzled-related protein-2 and -3 has a key role in the decreased osteoblast (OB) activity associated with multiple myeloma (MM) bone disease. We provide evidence that another Wnt antagonist, sclerostin, an osteocyte-expressed negative regulator of bone formati...
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Citations
... 60 and SOST,61 showed a significant decrease after 1 year of treatment. Furthermore, CTX, which reflects bone destruction, showed a significant decrease only in patients who received long-term treatment. ...
The use of lenalidomide in frontline therapy for patients with newly diagnosed multiple myeloma (MM) has increased the number of those who become refractory to lenalidomide at second line. In this context, we assessed the efficacy of daratumumab in combination with ixazomib and dexamethasone (Dara‐Ixa‐dex) in the prospective phase 2 study DARIA. Eligible patients had relapsed/refractory MM (RRMM) after one prior line with a lenalidomide‐based regimen. The primary endpoint was overall response rate (ORR). Secondary endpoints included survival outcomes, safety and changes in biomarkers of bone metabolism. Overall, 50 patients were enrolled (median age 69 years, 56% males). 32 (64%) patients were refractory to lenalidomide, and 17 (34%) had undergone autologous transplant. The ORR was 64% (n = 32); whereas 17 (34%) had a very good partial response or better. The median time to first response was 1.0 month. After a median follow‐up of 23.4 months, the median PFS and OS were 8.1 and 39.2 months, respectively. Furthermore, significant changes in markers of bone metabolism became evident as early as at 6 months on treatment. Regarding safety, 21 (42%) patients had ≥1 grade 3/4 adverse event (AE); the most common was thrombocytopenia (n = 9, 18%). 14 (28%) patients had ≥1 serious AE (SAE), the most common being acute kidney injury and pneumonia (n = 2, each). Four patients died due to infections. In conclusion, second‐line treatment with Dara‐Ixa‐dex in patients with RRMM pre‐treated with a lenalidomide‐based regimen resulted in rapid responses along with a favorable effect on bone metabolism.
... Studies have shown that serum sclerostin levels depend on environmental factors, including genetic aspects, age, sex, adiposity, and renal function [54]. Besides, in pathological conditions, chronic inflammation and RANKL may be an additional mechanism of sclerostin elevation, including multiple myeloma [55] and rheumatoid arthritis [56]. Pro-inflammatory cytokine (TNF-alpha) can also induce sclerostin expression [57]. ...
Dickkopf-1 (DKK-1) has been considered a master regulator of bone remodeling. As precursors of osteoclasts (OCs), myeloid-derived suppressor cells (MDSCs) were previously shown to participate in the process of bone destruction in rheumatoid arthritis (RA). However, the role of DKK-1 and MDSCs in RA is not yet fully understood. We investigated the relevance between the level of DKK-1 and the expression of MDSCs in different tissues and joint destruction in RA patients and collagen-induced arthritis (CIA) mouse models. Furthermore, the CIA mice were administered recombinant DKK-1 protein. The arthritis scores, bone destruction, and the percentage of MDSCs in the peripheral blood and spleen were monitored. In vitro, the differentiation of MDSCs into OCs was intervened with recombinant protein and inhibitor of DKK-1. The number of OCs differentiated and the protein expression of the Wnt/β-catenin signaling pathway were explored. The level of DKK-1 positively correlates with the frequency of MDSCs and bone erosion in RA patients and CIA mice. Strikingly, recombinant DKK-1 intervention significantly exacerbated arthritis scores and bone destruction, increasing the percentage of MDSCs in the peripheral blood and spleen in CIA mice. In vitro experiments showed that recombinant DKK-1 promoted the differentiation of MDSCs into OCs, reducing the expression of β-catenin and TCF4 and increasing the expression of CyclinD1. In contrast, the DKK-1 inhibitor had the opposite effect. Our findings highlight that DKK-1 promoted MDSCs expansion in RA and enhanced the differentiation of MDSCs into OCs via targeting the Wnt/β-catenin pathway, aggravating the bone destruction in RA.
... Previous studies have demonstrated that the suppression of osteoblast function and enhancement of osteoclast activity plays significant role in the pathogenesis of myeloma bone disease [5]. Various pathways participate in the bone remodeling process, such as the receptor activator of nuclear factor (NF)-κB (RANK)/ RANK ligand (RANKL) signaling pathway, Notch signaling pathway and tumor necrosis factor (TNF) superfamily, which are implicated in increased osteoclast activity, as well as the Wingless and integration-1 (WNT) signaling pathway, Dick-kopf-1 (DKK1) pathway and sclerostin pathway, which are implicated in decreased osteoblast activity [6][7][8]. ...
RUNX2 is a transcription factor that participates in osteoblast differentiation and chondrocyte maturation and plays an important role in the invasion and metastasis of cancers. With the deepening of research, evidence has indicated the correlation between RUNX2 and bone destruction in cancers. However, the mechanisms underlying its role in multiple myeloma remain unclear. By observing the induction effects of conditioned medium from myeloma cells on preosteoblasts (MC3T3-E1) and preosteoclasts (RAW264.7) and constructing myeloma-bearing mice, we found that RUNX2 promotes bone destruction in multiple myeloma. In vitro, conditioned medium from RUNX2-overexpressing myeloma cells reduced osteoblast activity and increased osteoclast activity. In vivo, RUNX2 expression was positively correlated with bone loss in myeloma-bearing mice. These results suggest that therapeutic inhibition of RUNX2 may protect against bone destruction by maintaining the balance between osteoblast and osteoclast activity in multiple myeloma.
... Cytokines aberrantly over-produced by MM cells, including macrophage inflammatory protein (MIP)-1α and interleukin (IL)-34 as well as MM cell adhesion up-regulate RANKL in BMSCs, which play a major role in the enhancement of osteoclastogenesis and bone resorption in MM [5][6][7]. In addition, factors over-produced by MM cells and/or their surrounding microenvironment in bone such as soluble Wnt inhibitors, IL-3, IL-7, tumor necrosis factor alfa (TNF-α), activin A, and transforming growth factor beta (TGF-β) have been demonstrated to suppress osteoblastic differentiation [8][9][10][11][12][13]. Therefore, multiple factors act together to eventually develop extensive bone destruction in MM (Fig. 2). ...
Introduction:
Multiple myeloma (MM) is a malignancy of plasma cells with characteristic bone disease. Despite recent great strides achieved in MM treatment owing to the implementation of new anti-MM agents, MM is still incurable and bone destruction remains a serious unmet issue in patients with MM.
Approach:
In this review, we will summarize and discuss the mechanisms of the formation of bone disease in MM and the available preclinical and clinical evidence on the treatment for MM bone disease.
Conclusions:
MM cells produce a variety of cytokines to stimulate receptor activator of nuclear factor-κB ligand-mediated osteoclastogenesis and suppress osteoblastic differentiation from bone marrow stromal cells, leading to extensive bone destruction with rapid loss of bone. MM cells alter the microenvironment through bone destruction where they colonize, which in turn favors tumor growth and survival, thereby forming a vicious cycle between tumor progression and bone destruction. Denosumab or zoledronic acid is currently recommended to be administered at the start of treatment in newly diagnosed patients with MM with bone disease. Proteasome inhibitors and the anti-CD38 monoclonal antibody daratumumab have been demonstrated to exert bone-modifying activity in responders. Besides their anti-tumor activity, the effects of new anti-MM agents on bone metabolism should be more precisely analyzed in patients with MM. Because prognosis in patients with MM has been significantly improved owing to the implementation of new agents, the therapeutic impact of bone-modifying agents should be re-estimated in the era of these new agents.
... B lymphocytes could promote osteoclastogenesis by up-regulating RANKL expression (Giuliani et al. 2002), and plasma cells differentiated from malignant B lymphocytes release proteases such as sclerostin and Dickkopf Wnt signaling pathway inhibitor-1 (DKK-1) to suppress OBs differentiation (Colucci et al. 2011). B lymphocytes in rheumatoid arthritis mice secrete high levels of the OBs inhibitors CCL-3 and TNF (Sun et al. 2018). ...
Osteoradionecrosis of the jaws (ORNJ) is a severe complication that occurs after radiotherapy of head and neck malignancies. Clinically, conservative treatments and surgeries for ORNJ exhibited certain therapeutic effects, whereas the regenerative disorder of the post-radiation jaw remains a pending problem to be solved. In recent years, the recognition of the role of the immune microenvironment has led to a shift from an osteoblasts (OBs) or bone marrow mesenchymal stromal cells (BMSCs)-centered view of bone regeneration to the concept of a complicated microecosystem that supports bone regeneration. Current advances in osteoimmunology have uncovered novel targets within the immune microenvironment to help improve various regeneration therapies, notably therapies potentiating the interaction between BMSCs and immune cells. However, these researches lack a thorough understanding of the immune microenvironment and the interaction network of immune cells in the course of bone regeneration, especially for the post-operative defect of ORNJ. This review summarized the composition of the immune microenvironment during bone regeneration, how the immune microenvironment interacts with the skeletal system, and discussed existing and potential strategies aimed at targeting cellular and molecular immune microenvironment components.
... In recent years, preclinical studies have shown pathological bone turnover marker (BTM) signalling between MM and bone stromal cells as a driver of MM bone disease [6]. Namely, osteocytes secrete sclerostin [7] and MM cells (as well as bone and stromal cells) release Dickkopf-1 secreted glycoprotein (DKK1) [8], both are Wnt inhibitors that suppress osteoblast-mediated bone formation. Furthermore, MM cells induce increased receptor activators of nuclear factor kappa B ligand (RANK-L) expression and inhibit production of its antagonist osteoprotegerin (OPG) by stromal cells, favouring osteoclast-mediated bone destruction [9,10]. ...
Simple Summary
Whilst multiple myeloma (MM) remains incurable, two clinical priorities are to prolong remission and reduce complications, of which fragility fractures are a major source of morbidity. To this end, there is the need to develop biomarkers that can accurately track tumour burden and bone loss to guide treatment decisions. Here, we conducted a pilot feasibility study exploring the value of novel serum bone turnover and plasma cell burden markers and Diffusion-Weighted Magnetic Resonance Imaging (DW-MRI) when added to standard clinical assessment in patients with MM, monoclonal gammopathy of undetermined significance (MGUS) and smouldering MM (SMM). We show serum DKK1 and BCMA as possible correlates of tumour burden, and that serum sclerostin may correlate with bone mineral density. Furthermore, we validate DW-MRI in longitudinal assessment of tumour volume. Our study highlights emerging serum and radiological biomarkers for assessment of tumour burden and bone loss, which require further study in larger cohorts to validate these findings and understand their clinical utility.
Abstract
Novel biomarkers for tumour burden and bone disease are required to guide clinical management of plasma cell dyscrasias. Recently, bone turnover markers (BTMs) and Diffusion-Weighted Magnetic Resonance Imaging (DW-MRI) have been explored, although their role in the prospective assessment of multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) is unclear. Here, we conducted a pilot observational cohort feasibility study combining serum BTMs and DW-MRI in addition to standard clinical assessment. Fifty-five patients were recruited (14 MGUS, 15 smouldering MM, 14 new MM and 12 relapsed MM) and had DW-MRI and serum biomarkers (P1NP, CTX-1, ALP, DKK1, sclerostin, RANKL:OPG and BCMA) measured at baseline and 6-month follow-up. Serum sclerostin positively correlated with bone mineral density (r = 0.40−0.54). At baseline, serum BCMA correlated with serum paraprotein (r = 0.42) and serum DKK1 correlated with serum free light chains (r = 0.67); the longitudinal change in both biomarkers differed between International Myeloma Working Group (IMWG)-defined responders and non-responders. Myeloma Response Assessment and Diagnosis System (MY-RADS) scoring of serial DW-MRI correlated with conventional IMWG response criteria for measuring longitudinal changes in tumour burden. Overall, our pilot study suggests candidate radiological and serum biomarkers of tumour burden and bone loss in MM/MGUS, which warrant further exploration in larger cohorts to validate the findings and to better understand their clinical utility.
... Among these, the most highly recognized are Dkk-1, a member of the family of Dickkopfs proteins, the Wnt inhibitory factor (Wif-1), sclerostin and sFRPs. By binding to LRP5/6 receptors of the canonical Wnt pathway, these soluble factors are able to arrest OBs differentiation [101] (Figure 2). ...
Multiple myeloma (MM) is a monoclonal gammopathy characterized by biological heterogeneity and unregulated proliferation of plasma cells (PCs) in bone marrow (BM). MM is a multistep process based on genomic instability, epigenetic dysregulation and a tight cross-talk with the BM microenvironment that plays a pivotal role supporting the proliferation, survival, drug-resistance and homing of PCs. The BM microenvironment consists of a hematopoietic and a non-hematopoietic compartment, which cooperate to create a tumor environment. Among the non-hematopoietic component, mesenchymal stromal cells (MSCs) and osteoblasts (OBs) appear transcriptionally and functionally different in MM patients compared to healthy donors (HDs) and to patients with pre-malignant monoclonal gammopathies. Alterations of both MSCs and OBs underly the osteolytic lesions that characterize myeloma-associated bone disease. In this review, we will discuss the different characteristics of MSCs and OBs in MM patients, analyzing the transcriptome, the deregulated molecular pathways and the role performed by miRNAs and exosome in the pathophysiology of MM.
... We found that activation of Wnt-β-catenin enhanced cell proliferation whereas it slightly reduced catecholamine synthesis in PC12 cells, sclerostin was expressed in PC12, and the expression levels were upregulated by BMPs. Sclerostin, a negative regulator of Wnt signaling, plays an important role in malignant diseases with bone involvement [15][16][17][18]. Activation of the Wnt-β-catenin pathway promoted cell proliferation and blockade of the endogenous Wnt-β-catenin pathway by sclerostin as well as XAV939 reduced cell proliferation. ...
... Sclerostin is prominently produced by osteocytes and functions as a key regulator of normal bone remodeling, which inhibits bone formation by inhibiting Wnt signaling [21]. Furthermore, sclerostin is expressed in certain pathological conditions, including malignant diseases with bone involvement [15][16][17][18]. Sclerostin mRNA and protein expression has been reported in multiple myeloma cell lines (H929, RPMI-8226, U266, and Karpas909) and myeloma cells derived from patients with multiple myeloma [16]. ...
... Furthermore, sclerostin is expressed in certain pathological conditions, including malignant diseases with bone involvement [15][16][17][18]. Sclerostin mRNA and protein expression has been reported in multiple myeloma cell lines (H929, RPMI-8226, U266, and Karpas909) and myeloma cells derived from patients with multiple myeloma [16]. The expression levels are higher in myeloma cells isolated from multiple myeloma patients with osteolytic disease than in those without bone disease [15]. ...
Pheochromocytomas and paragangliomas (PPGLs) are classified into 3 major categories with distinct driver genes: pseudohypoxia, kinase signaling, and Wnt-altered subtypes. PPGLs in the Wnt-altered subtype are sporadic and tend to be aggressive with metastasis, where somatic gene fusions affecting mastermind-like 3 (MAML3) and somatic mutations in cold shock domain containing E1 (CSDE1) cause overactivation of Wnt-β-catenin signaling. However, the relation between Wnt-β-catenin signaling and the biological behavior of PPGLs remains unexplored. In rat pheochromocytoma PC12 cells, Wnt3a treatment enhanced cell proliferation and suppressed mRNA expression of tyrosine hydroxylase (TH), i.e. the rate-limiting enzyme of catecholamine biosynthesis, and dopamine secretion. We identified the expression of sclerostin in PC12 cells, which is known as an osteocyte-derived negative regulator for Wnt signaling-driven bone formation. Inhibition of endogenous Wnt pathway by XAV939 or sclerostin resulted in attenuated cell proliferation and increased TH expression. Furthermore, Wnt3a pretreatment suppressed bone morphogenetic protein (BMP)-induced Smad1/5/9 phosphorylation whereas BMPs enhanced sclerostin expression in PC12 cells. In the Wnt-altered subtype, the increased Wnt-β-catenin pathway may contribute the aggressive clinical behavior with reduced catecholamine production. Furthermore, up-regulated expression of sclerostin by BMPs may explain the osteolytic metastatic lesions observed in metastatic PPGLs.
... 30 In a coculture system of BMSCs and MM cells secreting sclerostin, maturation and differentiation of osteoblasts were significantly inhibited. 31 Patients with MM have significantly higher levels of sclerostin than those with MGUS, which is associated with lower osteoblast function and shorter survival. 32,33 Researchers also confirmed that sclerostin started to increase 4 months before relapse and was higher than that at complete response. ...
Bone disease is the most common complication in patients with multiple myeloma (MM), and it may lead to skeletal‐related events (SREs) such as bone pain, pathological fractures, and spinal cord compression, which impair a patients' quality of life and survival. The pathogenesis of myeloma bone disease (MBD) involves disruption of bone reconstitution balance including excessive activation of osteoclasts, inhibition of osteoblasts, and participation of osteocytes and bone marrow stromal cells. Various factors, such as the receptor activator of nuclear factor‐κB ligand (RANKL)/osteoprotegerin (OPG), dickkopf‐1 (DKK‐1), sclerostin, and activin‐A, are involved in the development of MBD. Bisphosphonates and the anti‐RANKL antibody denosumab are currently the main treatment options for MBD, delaying the onset of SREs. Denosumab is preferred in patients with MM and renal dysfunction. Although effective drugs have been approved, antimyeloma therapy is the most important method for controlling bone disease. Multiple myeloma is the leading cause of destructive bone disease. Overactivation of osteoclasts and suppression of osteoblasts are involved in the pathogenesis of myeloma bone disease. Bisphosphonates and denosumab are cornerstones to prevent skeletal‐related events. Multiple myeloma is the leading cause of destructive bone disease. Overactivation of osteoclasts and suppression of osteoblasts are involved in the pathogenesis of myeloma bone disease. Bisphosphonates and denosumab are cornerstones to prevent skeletal‐related events. Pathophysiology and main treatment options for myeloma bone disease.
... DKK1 upregulation leads to increased SOST expression, whereas both molecules have a synergistic inhibitory impact on bone growth [30]. SOST is expressed by both myeloma cells and osteocytes, and it acts as a negative regulator of the Wnt pathway and, consequently, bone formation [31][32][33]. Patients with MM and increased SOST levels present with impaired bone turnover, advanced disease stage and adverse prognosis [34,35]. However, SOST levels did not show any significant changes with daratumumab treatment in our study. ...
Simple Summary
Multiple myeloma (MM) is characterized by the presence of deregulated bone metabolism. Restoring bone turnover is essential for patients with MM. We prospectively evaluated the impact of the anti-CD38 monoclonal antibody daratumumab on markers of bone remodeling among patients with relapsed/refractory MM. Overall, daratumumab improved bone turnover by favoring bone formation.
Abstract
Biomarkers of bone turnover in serum are suggestive of bone dynamics during treatment in multiple myeloma (MM). We evaluated the role of daratumumab on bone remodeling among patients with relapsed/refractory MM in the prospective, open-label, phase 2 study REBUILD. Daratumumab was administered according to the approved indication. A total of 33 out of 57 enrolled patients completed 4 months of treatment. The median percent change from baseline to 4 months in C-terminal cross-linking telopeptide of type 1 collagen (CTX) (primary endpoint) was 3.9%, with 13 (39.4%) and 11 (33.3%) patients showing at least 20% and 30% reduction in CTX levels, respectively. The median percent decrease from baseline to 4 months in tartrate resistant acid phosphatase 5b (TRACP-5b) levels (co-primary endpoint) was 2.6%, with 10 (30.3%) and 6 (18.2%) patients showing at least 20% and 30% reduction in TRACP-5b levels, respectively. However, the changes in these markers of bone catabolism were not statistically significant. Furthermore, the levels of osteocalcin, bone-specific alkaline phosphatase and procollagen type-I N-pro-peptide (bone formation markers) increased from baseline to 4 months (secondary endpoints) by 18.4%, 92.6% and 10.2%, respectively. Furthermore, the median levels of dickkopf-1 and C-C motif ligand-3 showed a significant decrease at 4 months by 17.5% and 16.0%, respectively. In conclusion, daratumumab improved bone turnover by inducing bone formation and reducing osteoblast inhibition.
