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Role of Wnt signaling and sclerostin in bone and as therapeutic targets in skeletal disorders

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Abstract

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.

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Acknowledgements

The authors are grateful to the Fondazione FIRMO Onlus for the support.

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Authors and Affiliations

  1. Fondazione FIRMO Onlus, Italian Foundation for the Research on Bone Diseases, Via San Gallo 123, 50129, Florence, Italy

    Francesca Marini & Maria Luisa Brandi

  2. Donatello Bone Clinic, Villa Donatello Hospital, Sesto Fiorentino, Florence, Italy

    Francesca Giusti & Maria Luisa Brandi

  3. Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

    Francesca Giusti & Gaia Palmini

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Marini, F., Giusti, F., Palmini, G. et al. Role of Wnt signaling and sclerostin in bone and as therapeutic targets in skeletal disorders. Osteoporos Int 34, 213–238 (2023). https://doi.org/10.1007/s00198-022-06523-7

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