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Review
. 2024 Jun 19:47:39-49.
doi: 10.1016/j.jot.2024.05.004. eCollection 2024 Jul.

Sclerostin inhibition in rare bone diseases: Molecular understanding and therapeutic perspectives

Tao Xiaohui  1   2   3   4 , Luyao Wang  1   2   3   4 , Xin Yang  1   2   3   4 , Hewen Jiang  2   5 , Ning Zhang  2   5 , Huarui Zhang  2   5 , Dijie Li  1   2   3   4 , Xiaofei Li  1   2   3   4 , Yihao Zhang  2   5 , Shenghang Wang  1   2   3   4 , Chuanxin Zhong  1   2   3   4 , Sifan Yu  2   5 , Meishen Ren  1   2   3   4 , Meiheng Sun  1   2   3   4 , Nanxi Li  1   2   3   4 , Tienan Chen  1   2   3   4 , Yuan Ma  1   2   3   4 , Fangfei Li  1   2   3   4 , Jin Liu  1   2   3   4 , Yuanyuan Yu  1   2   3   4 , Hua Yue  6 , Zhenlin Zhang  6 , Ge Zhang  1   2   3   4
Affiliations
Review

Sclerostin inhibition in rare bone diseases: Molecular understanding and therapeutic perspectives

Tao Xiaohui et al. J Orthop Translat. .

Abstract

Sclerostin emerges as a novel target for bone anabolic therapy in bone diseases. Osteogenesis imperfecta (OI) and X-linked hypophosphatemia (XLH) are rare bone diseases in which therapeutic potential of sclerostin inhibition cannot be ignored. In OI, genetic/pharmacologic sclerostin inhibition promoted bone formation of mice, but responses varied by genotype and age. Serum sclerostin levels were higher in young OI-I patients, while lower in adult OI-I/III/IV. It's worth investigating whether therapeutic response of OI to sclerostin inhibition could be clinically predicted by genotype and age. In XLH, preclinical/clinical data suggested factors other than identified FGF23 contributing to XLH. Higher levels of circulating sclerostin were detected in XLH. Sclerostin inhibition promoted bone formation in Hyp mice, while restored phosphate homeostasis in age-/gender-dependent manner. The role of sclerostin in regulating phosphate metabolism deserves investigation. Sclerostin/FGF23 levels of XLH patients with/without response to FGF23-antibody warrants study to develop precise sclerostin/FGF23 inhibition strategy or synergistic/additive strategy. Notably, OI patients were associated with cardiovascular abnormalities, so were XLH patients receiving conventional therapy. Targeting sclerostin loop3 promoted bone formation without cardiovascular risks. Further, blockade of sclerostin loop3-LRP4 interaction while preserving sclerostin loop2-ApoER2 interaction could be a potential precise sclerostin inhibition strategy for OI and XLH with cardiovascular safety. The Translational Potential of this Article. Preclinical data on the molecular understanding of sclerostin inhibition in OI and therapeutic efficacy in mouse models of different genotypes, as well as clinical data on serum sclerostin levels in patients with different phenotypes of OI, were reviewed and discussed. Translationally, it would facilitate to develop clinical prediction strategies (e.g. based on genotype and age, not just phenotype) for OI patients responsive to sclerostin inhibition. Both preclinical and clinical data suggested sclerostin as another factor contributing to XLH, in addition to the identified FGF23. The molecular understanding and therapeutic effects of sclerostin inhibition on both promoting bone anabolism and improving phosphate homostasis in Hyp mice were reviewed and discussed. Translationaly, it would facilitate the development of precise sclerostin/FGF23 inhibition strategy or synergistic/additive strategy for the treatment of XLH. Cardiovascular risk could not be ruled out during sclerostin inhibition treatment, especially for OI and XLH patients with cardiovascular diseases history and cardiovascular abnormalities. Studies on the role of sclerostin in inhiting bone formation and protecting cardiovascular system were reviewed and discussed. Translationaly, blockade of sclerostin loop3-LRP4 interaction while preserving sclerostin loop2-ApoER2 interaction could be a potential precise sclerostin inhibition strategy for OI and XLH with cardiovascular safety.

Keywords: Cardiovascular safety; Loops; Osteogenesis imperfecta (OI); Sclerostin; Sclerostin inhibition; Therapeutic perspectives; X-linked hypophosphatemia (XLH).

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Image 1
Graphical abstract
Figure 1
Figure 1
Available drugs for the treatment of osteogenesis imperfecta.
Figure 2
Figure 2
Mechanisms of phosphorus metabolism in the bone and kidney, which could be antagonized by sclerostin inhibition.
Figure 3
Figure 3
Distinctive role of sclerostin loops in bone and cardiovascular system.
See this image and copyright information in PMC

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