Summary

Wnt signaling and its bone tissue–specific inhibitor sclerostin are key regulators of bone homeostasis. The therapeutic potential of anti-sclerostin antibodies (Scl-Abs), for bone mass recovery and fragility fracture prevention in low bone mass phenotypes, has been supported by animal studies. The Scl-Ab romosozumab is currently used for osteoporosis treatment.

Introduction

Wnt signaling is a key regulator of skeletal development and homeostasis; germinal mutations affecting genes encoding components, inhibitors, and enhancers of the Wnt pathways were shown to be responsible for the development of rare congenital metabolic bone disorders. Sclerostin is a bone tissue–specific inhibitor of the Wnt/β-catenin pathway, secreted by osteocytes, negatively regulating osteogenic differentiation and bone formation, and promoting osteoclastogenesis and bone resorption.

Purpose and methods

Here, we reviewed current knowledge on the role of sclerostin and Wnt pathways in bone metabolism and skeletal disorders, and on the state of the art of therapy with sclerostin-neutralizing antibodies in low-bone-mass diseases.

Results

Various in vivo studies on animal models of human low-bone-mass diseases showed that targeting sclerostin to recover bone mass, restore bone strength, and prevent fragility fracture was safe and effective in osteoporosis, osteogenesis imperfecta, and osteoporosis pseudoglioma. Currently, only treatment with romosozumab, a humanized monoclonal anti-sclerostin antibody, has been approved in human clinical practice for the treatment of osteoporosis, showing a valuable capability to increase BMD at various skeletal sites and reduce the occurrence of new vertebral, non-vertebral, and hip fragility fractures in treated male and female osteoporotic patients.

Conclusions

Preclinical studies demonstrated safety and efficacy of therapy with anti-sclerostin monoclonal antibodies in the preservation/restoration of bone mass and prevention of fragility fractures in low-bone-mass clinical phenotypes, other than osteoporosis, to be validated by clinical studies for their approved translation into prevalent clinical practice.

中文翻译：

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Wnt 信号传导和硬化蛋白在骨骼中的作用以及作为骨骼疾病治疗靶点的作用

概括

Wnt 信号传导及其骨组织特异性抑制剂硬化素是骨稳态的关键调节剂。动物研究支持了抗硬化蛋白抗体 (Scl-Abs) 在低骨量表型中用于骨量恢复和预防脆性骨折的治疗潜力。Scl-Ab romosozumab 目前用于治疗骨质疏松症。

介绍

Wnt 信号是骨骼发育和体内平衡的关键调节剂；影响编码 Wnt 通路组分、抑制剂和增强子的基因的生发突变被证明是导致罕见的先天性代谢性骨疾病的原因。硬化蛋白是 Wnt/β-catenin 通路的骨组织特异性抑制剂，由骨细胞分泌，负向调节成骨分化和骨形成，促进破骨细胞生成和骨吸收。

目的和方法

在这里，我们回顾了目前关于硬化素和 Wnt 通路在骨代谢和骨骼疾病中的作用的知识，以及硬化素中和抗体在低骨量疾病中的治疗现状。

结果

对人类低骨量疾病动物模型的各种体内研究表明，靶向硬化蛋白以恢复骨量、恢复骨强度和预防脆性骨折在骨质疏松症、成骨不全症和骨质疏松性假胶质瘤中是安全有效的。目前，只有 romosozumab 是一种人源化单克隆抗硬化蛋白抗体，已被批准用于治疗骨质疏松症的人体临床实践，显示出增加各种骨骼部位 BMD 和减少新椎体、非椎体发生率的宝贵能力。和治疗的男性和女性骨质疏松症患者的髋部脆性骨折。

结论

临床前研究表明抗硬化蛋白单克隆抗体治疗在骨质疏松症以外的低骨量临床表型中保存/恢复骨量和预防脆性骨折的安全性和有效性，将通过临床研究对其批准的翻译进行验证进入普遍的临床实践。