Wnt signaling in bone formation and its therapeutic potential for bone diseases

Kim, Jeong Hwan; Liu, Xing; Wang, Jinhua; Chen, Xiang; Zhang, Hongyu; Kim, Stephanie H.; Cui, Jing; Li, Ruidong; Zhang, Wenwen; Kong, Yuhan; Zhang, Jiye; Shui, Wei; Lamplot, Joseph D.; Rogers, Mary Rose; Zhao, Chen; Wang, Ning; Rajan, Prashant V.; Tomal, Justin; Statz, Joseph M.; Wu, Ningning; Luu, Hue H.; Haydon, Rex C.; He, Tong‐Chuan

doi:10.1177/1759720x12466608

Cited by 292 publications

(260 citation statements)

References 155 publications

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“…Knowledge gained from both genetic diseases, SOST1 and VBD, has led to the development of novel treatment strategies against osteoporosis by using humanized antibodies against sclerostin to counteract the osteocatabolic effect of sclerostin (Kim et al 2013;Clarke 2014). Romosozumab is currently in phase II clinical trial, whereas a phase I trial of blosozumab is completed.…”

Section: Gain Of Bone Mass In Camurati -Engelmann Diseasementioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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The transforming growth factor b (TGF-b) family of signaling molecules, which includes TGF-bs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-b family members play different roles in these tissues, and their activities are often balanced with those of other TGF-b family members and by interactions with other signaling pathways. Perturbations in TGF-b family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-b family of signaling mediators and the extracellular matrix in connective tissues.T he transforming growth factor b (TGF-b) family of cytokines comprises the three TGF-b proteins (TGF-b1, TGF-b2, and TGFb3) and related growth and differentiation factors such as activins, inhibins, bone morphogenic proteins (BMPs), and growth and differentiation factors (GDFs). These molecules play critical roles both in normal development and in several pathological conditions, including inflammation, fibrosis, and cancer (reviewed in Li and Flavell 2006;Gordon and Blobe 2008;Ikushima and Miyazono 2010). This review focuses on the role of these proteins in development and homeostasis of the skeleton and other connective tissues (summarized in Fig. 1) and on the diseases that ensue when these pathways are altered. Aberrant signaling in these pathways has been associated with common connective 6 These authors contributed equally to this work.

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Section: Gain Of Bone Mass In Camurati -Engelmann Diseasementioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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“…Osteoblasts express VEGF and both VEGF-A receptors, which are upregulated by hypoxia. The overexpression of HIF-1α by osteoblasts leads to increased angiogenesis and osteogenesis, coupled by osteoblast-generated VEGF (37). Wnt signaling is osteogenic by promoting mesenchymal stem cell differentiation, and its inactivation leads to osteoporosis (37).…”

Section: Hypoxia In Systemic Sclerosis: the Hif Pathway And Its Dysrementioning

confidence: 99%

“…The overexpression of HIF-1α by osteoblasts leads to increased angiogenesis and osteogenesis, coupled by osteoblast-generated VEGF (37). Wnt signaling is osteogenic by promoting mesenchymal stem cell differentiation, and its inactivation leads to osteoporosis (37). Also, the endothelial-myofibroblast transition involves the canonical Wnt and Notch signaling pathways, and dysregulated Wnt signaling is involved in the pathogenesis of SSc-associated fibrosis (37).…”

Section: Hypoxia In Systemic Sclerosis: the Hif Pathway And Its Dysrementioning

confidence: 99%

“…Wnt signaling is osteogenic by promoting mesenchymal stem cell differentiation, and its inactivation leads to osteoporosis (37). Also, the endothelial-myofibroblast transition involves the canonical Wnt and Notch signaling pathways, and dysregulated Wnt signaling is involved in the pathogenesis of SSc-associated fibrosis (37). The Wnt canonical pathway is activated by Ang, angiopoietin; ANGTPL, angiopoietin-like protein; BMP, bone morphogenetic protein; CTGF, connective tissue growth factor; GDF, growth differentiation factor; HIF, hypoxia-inducible factor; M-CSF, macrophage colony-stimulating factor; NVC, nailfold videocapillaroscopy; PDGF, platelet-derived growth factor; SSc, systemic sclerosis; TGF, transforming growth factor; VEGF, vascular endothelial growth factor.…”

Section: Hypoxia In Systemic Sclerosis: the Hif Pathway And Its Dysrementioning

confidence: 99%

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Acroosteolysis in systemic sclerosis: An insight into hypoxia-related pathogenesis

Siao-Pin

Damian

Muntean

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Acro-osteolysis, or bony resorption of the terminal digital tufts, is a well-recognized, but under-researched, feature of systemic sclerosis. The mechanisms that disturbs local homeostatic balance of bone formation and resorption in favor of osteoclast activation and pathological bone loss remain to be established. Vascular alterations and reduced capillary density impair tissue oxygenation in systemic sclerosis, and the resulting hypoxia might contribute directly to the disease progression. In this paper we summarize the current evidence for hypoxia as the common pathophysiological denominator of digital vasculopathy and enhanced osteoclastic activity in systemic sclerosis-associated acroosteolysis. The hypoxia-inducible transcription factor HIF-1α and VEGF signaling has a critical role in regulating osteoclastic bone-resorption and angiogenesis, and increased osteoclastogenesis and higher VEGF levels may contribute to acroosteolysis in systemic sclerosis. The cells of the osteoblast lineage also have important roles in angiogenic-osteogenic coupling. The research in this field might help limiting the disability associated with the disease.

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“…Although small animal models cannot directly mimic the formation of clinically relevant HO, each type of animal study provides the opportunity to better understand the pathophysiology and pathogenesis under unique circumstances. A comprehensive evaluation of the mechanistic pathways of bone growth, healing, and complications that may contribute to HO is beyond the scope of this review but some of the discussions are provided for further investigation 28, 29, 30, 31, 32, 33, 34, 35, 36, 37. With improved understanding, better physical and pharmacological therapeutic protocols can be developed for use in human patients.…”

Section: Understanding the Ho Environmentmentioning

confidence: 99%