SOST expression is restricted to the great arteries during embryonic and neonatal cardiovascular development.

Spatial-temporal regulation of bone morphogenetic protein (BMP) and Wnt activity is essential for normal cardiovascular development, and altered activity of these growth factors causes maldevelopment of the cardiac outflow tract and great arteries. In the present study, we show that SOST, a Dan family member reported to antagonize BMP and Wnt activity, is expressed within the medial vessel wall of the great arteries containing smooth muscle cells. The ascending aorta, aortic arch, brachiocephalic artery, common carotids, and pulmonary trunk were all associated with SOST expressing smooth muscle cells, while the heart itself, including the valves, and more distal arteries, that is, pulmonary arteries, subclavian arteries, and descending aorta, were negative. SOST was expressed from embryonic day 15.5 up to the neonatal period. SOST expression, however, did not correspond with inhibition of Smad-dependent BMP activity or beta-catenin-dependent Wnt activity in the great arteries. Activity of both signaling pathways was already down-regulated before induction of SOST expression.     

Sclerostin Expression in Bile Ducts of Patients With Chronic Cholestasis May Influence the Bone Disease in Primary Biliary Cirrhosis

Sclerostin is involved in the regulation of osteoblastogenesis and little is known about its role in the development of bone disease in primary biliary cirrhosis (PBC), characterized by low bone formation. Therefore, we have assessed the circulating levels and the liver expression of sclerostin in this cholestatic disease. Serum sclerostin levels were measured in 79 women with PBC (mean age 60.6 ± 1.2 years) and in 80 control women. Lumbar and femoral bone mineral density (BMD), as well as parameters of mineral metabolism and bone remodeling, were measured. Moreover, sclerostin gene (SOST) expression in the liver was assessed by real‐time PCR in samples of liver tissue taken by biopsy in 11 PBC patients and in 5 normal liver specimens. Presence and distribution of sclerostin was evaluated in liver slices from 11 patients by immunohistochemistry. The severity of histologic lesions was assessed semiquantitatively in the same liver samples. PBC patients had higher sclerostin levels than controls (75.6 ± 3.9 versus 31.7 ± 1.6 pmol/L, p < 0.001). Serum sclerostin correlated inversely with markers of bone formation and resorption. Sclerostin mRNA in the liver was overexpressed compared with control samples (2.7‐fold versus healthy liver). Sclerostin was detected by immunohistochemistry in 7 of the 11 liver samples, mainly located in the bile ducts. Liver sclerostin was associated with the severity of cholangitis (p = 0.02) and indirectly with the degree of lobular inflammation (p = 0.03). Sclerostin mRNA expression was higher in samples that tested positive by immunohistochemistry and particularly in those with lobular granuloma (p = 0.02). The increased expression of sclerostin in the liver and the association with histologic cholangitis may explain the high serum levels of this protein in patients with PBC, thus suggesting that sclerostin may influence the decreased bone formation in this cholestatic disease. © 2016 American Society for Bone and Mineral Research.     

Localization of SOST/sclerostin in cementocytes in vivo and in mineralizing periodontal ligament cells in vitro

Jäger A, Götz W, Lossdörfer S, Rath‐Deschner B. Localization of SOST/sclerostin in cementocytes in vivo and in mineralizing periodontal ligament cells in vitro. J Periodont Res 2009; doi: 10.1111/j.1600‐0765.2009.01227.x. © 2009 John Wiley & Sons A/S Background and Objective: Cementum and bone are rather similar hard tissues, and osteocytes and cementocytes, together with their canalicular network, share many morphological and cell biological characteristics. However, there is no clear evidence that cementocytes have a function in tissue homeostasis of cementum comparable to that of osteocytes in bone. Recent studies have established an important role for the secreted glycoprotein sclerostin, the product of the SOST gene, as an osteocyte‐derived signal to control bone remodelling. In this study, we investigated the expression of sclerostin in cementocytes in vivo as well as the expression of SOST and sclerostin in periodontal ligament cell cultures following induction of mineralization. Material and Method: Immunolocalization of sclerostin was performed in decalcified histological sections of mouse and human teeth and alveolar bone. Additionally, periodontal ligament cells from human donors were cultured in osteogenic conditions, namely in the presence of dexamethasone, ascorbic acid and β‐glycerophosphate, for up to 3 wk. The induction of calcified nodules was visualized by von Kossa stain. SOST mRNA was detected by real‐time PCR, and the presence of sclerostin was verified using immunohistochemistry and western blots. Results: Expression of sclerostin was demonstrated in osteocytes of mouse and human alveolar bone. Distinct immunolocalization in the cementocytes was shown. In periodontal ligament cultures, following mineralization treatment, increasing levels of SOST mRNA as well as of sclerostin protein could be verified. Conclusion: The identification of SOST/sclerostin in cementocytes and mineralizing periodontal ligament cells adds to our understanding of the biology of the periodontium, but the functional meaning of these findings can only be unravelled after additional in vitro and in vivo studies.     

骨硬化蛋白单克隆抗体治疗骨质疏松

背景：骨硬化蛋白可负向调节骨代谢,其单克隆抗体可拮抗负向调节作用,在促进骨形成的同时抑制骨吸收。目的：旨在探讨骨硬化蛋白单克隆抗体在治疗骨质疏松中的作用机制及最新进展。方法：由第一作者应用计算机检索 PubMed、中国期刊全文数据库（CNKI）、维普数据库和万方数据库（2005年 5 月至 2013 年 5 月）相关文献。在标题、摘要、关键词中以＂osteoporosis,antibody,sclerostin,Wnt,SOST＂或＂骨质疏松,单克隆抗体,骨硬化蛋白,Wnt 通路＂为检索词进行检索。选择文章内容与骨硬化蛋白单克隆抗体有关者,同一领域文献则选择近期发表在权威杂志文章。结果与结论：初检得到 170 篇文献,根据纳入标准选择关于骨硬化蛋白单克隆抗体的 54 篇文献进行综述。骨硬化蛋白通过与 Wnt 经典信号通路共受体低密度脂蛋白受体相关蛋白 5/6 结合以阻断 Wnt 通路,从而抑制成骨细胞分化及矿化。其单克隆抗体通过与骨硬化蛋白特异性结合而间接促进骨形成、抑制骨吸收,在骨质疏松的治疗中有重大意义。同时,与其他治疗方法相比,骨硬化蛋白作用靶点的组织特异性及骨硬化蛋白单克隆抗体的结合特异性为其增加了应用优势。     

骨硬化蛋白:一个治疗骨质疏松的新靶点

高骨量疾病骨硬化症(sclerosteosis)和Van Buchem病由SOST基因表达缺失导致.由于SOST基因突变导致骨硬化蛋白不能表达或功能缺陷,可造成该病患者的过度骨形成,其作用机制与抑制Wnt信号转导通路相关.骨硬化蛋白通过与该通路共受体LRP5/6结合来阻断Wnt通路,进而对成骨细胞分化及矿化起抑制作用.由于骨硬化蛋白在抑制骨形成起关键作用且仅在骨组织表达,其单克隆抗体可用于治疗低骨量疾病如骨质疏松.     

Therapeutic approaches to myeloma bone disease: an evolving story

Bone disease is a major morbidity factor in patients with multiple myeloma and significantly affects their overall survival. A complex interplay between malignant plasma cells and other marrow cells results in the generation of a microenvironment capable of enhancing both tumor growth and bone destruction. Bisphosphonates have consistently reduced the incidence of skeletal-related events in patients with multiple myeloma and other osteotropic tumors as well. However, their use is burdened with side-effects, including the risks of osteonecrosis of the jaw and kidney failure, suggesting that they should be discontinued after prolonged administration. New molecular targets of cell cross-talk in myeloma bone marrow are therefore under intensive investigation and new drugs are being explored in preclinical and clinical studies of myeloma bone disease. Compounds targeting osteoclast activation pathways, such as receptor activator of nuclear factor-κB/receptor activator of nuclear factor-κB ligand/osteoprotegerin, B-cell activating factor, mitogen-activated protein kinase and macrophage inflammatory protein-1α/chemokine receptor for macrophage inflammatory protein-1α axes, or soluble agents that improve osteoblast differentiation by modulating specific inhibitors such as Dickkopf-1 and transforming growth factor-β, as well as novel approaches of cytotherapy represent a new generation of promising drugs for the treatment of myeloma bone disease.     

新疆绝经后2型糖尿病女性SOST蛋白表达在骨质疏松中诊断价值的研究

目的探讨SOST蛋白表达水平与骨代谢的关系及其在骨质疏松(osteoporosis,OP)中的诊断价值,为预防绝经后2型糖尿病(type 2 diabetes mellitus,T2DM)女性合并OP的发生提供依据。方法纳入对象为135例新疆绝经后女性,记录其年龄等一般基线资料;全自动生化分析仪测定空腹血糖(FPG)、碱性磷酸酶(ALP)等生化指标;双能X线吸收检测法(dual energy X-ray absorptiometry,DXA)测定股骨颈及腰椎(L1~4)骨密度(BMD);酶联免疫吸附法(ELISA)测定SOST蛋白的表达水平。结果(1)与A组(277.261±251.144)相比,B组(785.507±366.941)和D组(884.056±631.041)的SOST蛋白表达水平高于A组,差异具有统计学意义(P<0.01)。(2)通过绘制ROC曲线显示,SOST蛋白表达水平诊断OP的最佳临界点为0.479,其对应的SOST蛋白水平为851.31 pg/mL,敏感度为61.4%,特异性为86.5%,曲线下面积(AUC)为0.741(95%可信区间:0.656~0.827);(3)Pearson相关性分析显示,新疆绝经后T2DM女性SOST蛋白表达水平与BMD(L1~4)呈负相关(r=-0.239,P=0.005)。结论(1)新疆绝经后T2DM女性SOST蛋白表达水平与骨代谢有关,且SOST蛋白高表达是腰椎BMD(L1~4)降低的危险因素。(2)以SOST蛋白表达水平≥851.31 pg/mL为0P的诊断标准,有较大的AUC和更高的敏感性。     

Sclerostin Downregulation Globally by Naturally Occurring Genetic Variants,or Locally in Atherosclerotic Plaques,Does Not Associate With Cardiovascular Events in Humans

Inhibition of sclerostin increases bone formation and decreases bone resorption, leading to increased bone mass, bone mineral density, and bone strength and reduced fracture risk. In a clinical study of the sclerostin antibody romosozumab versus alendronate in postmenopausal women (ARCH), an imbalance in adjudicated serious cardiovascular (CV) adverse events driven by an increase in myocardial infarction (MI) and stroke was observed. To explore whether there was a potential mechanistic plausibility that sclerostin expression, or its inhibition, in atherosclerotic (AS) plaques may have contributed to this imbalance, sclerostin was immunostained in human plaques to determine whether it was detected in regions relevant to plaque stability in 94 carotid and 50 femoral AS plaques surgically collected from older female patients (mean age 69.6 ± 10.4 years). Sclerostin staining was absent in most plaques (67%), and when detected, it was of reduced intensity compared with normal aorta and was located in deeper regions of the plaque/wall but was not observed in areas considered relevant to plaque stability (fibrous cap and endothelium). Additionally, genetic variants associated with lifelong reduced sclerostin expression were explored for associations with phenotypes including those related to bone physiology and CV risk factors/events in a population-based phenomewide association study (PheWAS). Natural genetic modulation of sclerostin by variants with a significant positive effect on bone physiology showed no association with lifetime risk of MI or stroke. These data do not support a causal association between the presence of sclerostin, or its inhibition, in the vasculature and increased risk of serious cardiovascular events. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Wnt inhibitors Dkk1 and Sost are downstream targets of BMP signaling through the type IA receptor (BMPRIA) in osteoblasts

The bone morphogenetic protein (BMP) and Wnt signaling pathways both contribute essential roles in regulating bone mass. However, the molecular interactions between these pathways in osteoblasts are poorly understood. We recently reported that osteoblast‐targeted conditional knockout (cKO) of BMP receptor type IA (BMPRIA) resulted in increased bone mass during embryonic development, where diminished expression of Sost as a downstream effector of BMPRIA resulted in increased Wnt/β‐catenin signaling. Here, we report that Bmpr1a cKO mice exhibit increased bone mass during weanling stages, again with evidence of enhanced Wnt/β‐catenin signaling as assessed by Wnt reporter TOPGAL mice and TOPFLASH luciferase. Consistent with negative regulation of the Wnt pathway by BMPRIA signaling, treatment of osteoblasts with dorsomorphin, an inhibitor of Smad‐dependent BMP signaling, enhanced Wnt signaling. In addition to Sost, Wnt inhibitor Dkk1 also was downregulated in cKO bone. Expression levels of Dkk1and Sost were upregulated by BMP2 treatment and downregulated by Noggin. Moreover, expression of a constitutively active Bmpr1a transgene in mice resulted in the upregulation of both Dkk1 and Sost and partially rescued the Bmpr1a cKO bone phenotype. These effectors are differentially regulated by mitogen‐activated protein kinase (MAPK) p38 because pretreatment of osteoblasts with SB202190 blocked BMP2‐induced Dkk1 expression but not Sost. These results demonstrate that BMPRIA in osteoblasts negatively regulates endogenous bone mass and Wnt/β‐catenin signaling and that this regulation may be mediated by the activities of Sost and Dkk1. This study highlights several interactions between BMP and Wnt signaling cascades in osteoblasts that may be amenable to therapeutic intervention for the modification of bone mass density. © 2010 American Society for Bone and Mineral Research