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Biochemistry of Exercise Training: Effects on Bone
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Panagiota Klentrou, Rozalia Kouvelioti
Wnt signalling can be inhibited by sclerostin, resulting in reduced expression of bone formation genes (67, 82, 103, 121). Briefly, sclerostin binds to LRP 4 (139, 158), LRP 5, and LRP 6, thus preventing the Wnt-LRP 5/6–frizzled interaction. Sclerostin's binding to lipoprotein receptor proteins leads to the release of the GSK3/Axin/APC protein complex into the cytosol, causing the phosphorylation of β-catenin and its degradation by proteasome (67, 82, 103, 121, 143). In contrast, Wnt signalling is active in the absence of sclerostin and other Wnt antagonists. In this case, Wnt glycoproteins bind to frizzled receptors and LRP 5/6 co-receptors to form a complex. This causes recruitment of axin into the intracellular domain of the receptor complex and disruption of the APC–axin–GSK3–catenin complex by Dsh, leading to the accumulation of β-catenin in the cytosol. As explained earlier, β-catenin translocates to the nucleus and in association with the T-cell factor/lymphoid enhancer-binding factor (TCF/LEF), activates the expression of response genes related to bone formation (e.g., OPG) (104, 121).
Current and emerging pharmacological agents in the treatment of osteoporosis
Published in Peter V. Giannoudis, Thomas A. Einhorn, Surgical and Medical Treatment of Osteoporosis, 2020
James X. Liu, Thomas A. Einhorn
Sclerostin, produced primarily by osteocytes, is a monomeric glycoprotein that is a product of the SOST gene. SOST mRNA expression has been shown in bone marrow, cartilage, kidney, heart, and pancreatic tissue. The antagonist effects of sclerostin on the Wnt signaling pathway have been well established (21). The Wnt/β-catenin pathway has major effects on osteoblast differentiation and proliferation. Activation of the pathway involves binding of the Wnt ligand to LDL receptor-related proteins 5 and 6 (LRP5/LRP6 complex), which results in the inactivation of GSK-3β, which functions to target β-catenin. β-Catenin accumulates in the cytoplasm and is translocated into the nucleus where it upregulates the transcription of numerous target genes that stimulate differentiation of mesenchymal stem cells in the skeletal cells, which includes differentiation of osteoblasts and chondrocytes (22). Sclerostin inhibits the activity of the LRP5/LRP6 complex, preventing the binding of Wnt and stopping the Wnt/β-catenin signaling, thus inhibiting the osteoblast proliferation and differentiation.
Precision medicine in osteoporosis and bone diseases
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Fatmanur Hacievliyagil Kazanci, Fatih Kazanci, M. Ramazan Yigitoglu, Mehmet Gunduz
The osteocytes inhibit bone formation by producing sclerostin (van Bezooijen et al., 2004). Romosozumab is an antisclerostin antibody that has been reported to stimulate bone formation as well as inhibit bone resorption (Chapurlat, 2016). However, the antifracture efficacy of this drug remains to be determined in ongoing trials.
Current concepts underlying the pathophysiology of acute Charcot neuroarthropathy in the diabetic foot and ankle
Published in Expert Review of Clinical Immunology, 2020
Thomas H. Yates, Steven R. Cooperman, David Shofler, Devendra K. Agrawal
In another investigation by Folestad et al., the role of the Wnt/b-catenin pathway in acute CNA was considered. In addition to monitoring the serum levels of OPG and RANKL, serum levels of sclerostin, DKK-1, Wnt inhibitory factor-1, and Wnt ligand-1 were monitored as well. Sclerostin, DKK-1 and Wnt-1 were significantly lower in the CNA group versus the diabetic controls at inclusion. It was observed that DKK-1 and Wnt-1 responded to offloading therapy and increased in the CNA group, compatible with an increase in anabolic activity via the Wnt/B-catenin pathway. This is supported by the findings of Agholme et al. in 2010, 2011, and 2014 that the inhibition of DKK-1 and sclerostin improve healing of fractured bones [24–27]. Sclerostin, which plays a role in bone turnover, is suppressed, thereby promoting bone formation when mechanical loading occurs. Sclerostin levels classically increase during offloading, leading to bone resorption. However, in this study, sclerostin levels were identified to be decreased, even during offloading therapy for CNA. This finding of paradoxical sclerostin suppression may suggest that the gene coding for sclerostin expression is more complex than seen in mechanically unloaded and loaded states.
Emerging therapeutic targets for osteoporosis
Published in Expert Opinion on Therapeutic Targets, 2020
Luigi Gennari, Daniela Merlotti, Alberto Falchetti, Cristina Eller Vainicher, Roberta Cosso, Iacopo Chiodini
Sclerostin, an osteocyte secreted glycoprotein, inhibits OB differentiation and function by preventing the interactions between Wnt and its receptor, ultimately leading to phosphorylation and degradation of ß-catenin, which is a key regulator of Wnt target genes transcription [41]. Moreover, sclerostin promotes OC formation through a RANKL-dependent pathway [42]. Therefore, agents able to block sclerostin may increase bone formation and decrease bone resorption. Romosozumab, a monoclonal antibody against sclerostin, is administered monthly with a subcutaneous 210 mg regimen. In postmenopausal osteoporotic women, romosozumab reduced the risk of vertebral fracture (75%) and clinical fractures (36%), at 12 months and at 24 months after the transition to denosumab [43]. Moreover, romosozumab reduced the risk of vertebral, clinical, and non-vertebral fractures more than alendronate [44] and one-year romosozumab followed by 2 years denosumab showed a persistent BMD increase and anti-fracture efficacy [45].
Targeting fundamental aging mechanisms to treat osteoporosis
Published in Expert Opinion on Therapeutic Targets, 2019
Jack Feehan, Ahmed Al Saedi, Gustavo Duque
One of the therapeutic opportunities offered by the Wnt signaling pathway is that endogenous-secreted factors like sclerostin and proteins of the DKK1 family both bind to LRP4/5/6 and inhibit Wnt signaling, leading to decreased bone formation [21]. This has led to the development of anti-sclerostin antibodies (Romosozumab), which have entered the market for use in osteoporosis. Inhibition of sclerostin inhibits the negative regulation of bone formation allowing increased osteoblastic activity. More recently, investigators have created a bispecific antibody which binds to both DKK1 and sclerostin, and preliminary animal studies show promising increases in bone mass and acceleration of fracture repair [22]. However, while the Wnt signaling pathway is a promising approach for the development of anabolic treatments, safety concerns have been identified particularly regarding cardiovascular events, with increased risk of stroke and myocardial infarction. Additionally, some pre-clinical studies have shown that the deletion of some endogenous inhibitors of Wnt signaling, such as Wnt inhibitory factor 1, can lead to osteosarcoma [23] and gain of function mutations to LRP5 are associated with disease of high bone mass [24]. Despite this evidence of oncogenic effects, anti-sclerostin antibodies have also been shown to provide benefit in patients with breast cancer metastases, further broadening their scope of use [25].