The osteoprotective role of USP26 in coordinating bone formation and resorption.

Lianfu Deng,Bernhard Ryffel,Minglong Qiu,Leilei Chang,Changwei Li,Jin Qi,Lianfang Zhang

doi:10.1038/s41418-021-00904-x

Abstract

Bone homeostasis is maintained through a balance of bone formation by osteoblasts and bone resorption by osteoclasts. Ubiquitin-specific proteases (USPs) are involved in regulating bone metabolism by preserving bone formation or antagonizing bone resorption. However, the specific USPs that maintain bone homeostasis by orchestrating bone formation and bone resorption simultaneously are poorly understood. Here, we identified USP26 as a previously unknown regulator of bone homeostasis that coordinates bone formation and resorption. Mechanistically, USP26 stabilizes β-catenin to promote the osteogenic activity of mesenchymal cells (MSCs) and impairs the osteoclastic differentiation of bone myelomonocytes (BMMs) by stabilizing inhibitors of NF-κBα (IκBα). Gain-of-function experiments revealed that Usp26 supplementation significantly increased bone regeneration in bone defects in aged mice and decreased bone loss resulting from ovariectomy. Taken together, these data show the osteoprotective effect of USP26 via the coordination of bone formation and resorption, suggesting that USP26 represents a potential therapeutic target for osteoporosis.

Highlights

Bone homeostasis is maintained through a balance of bone formation by osteoblasts and bone resorption by osteoclasts [1]
We identified USP26 as a previously unknown regulator of bone homeostasis that simultaneously alters bone formation and resorption
USP26 was first identified by Wang et al, who isolated this gene from mouse spermatogonia [19]

Summary

Introduction

Bone homeostasis is maintained through a balance of bone formation by osteoblasts and bone resorption by osteoclasts [1]. An imbalance between the activity of osteoblasts and osteoclasts leads to improper bone formation and resorption, which underlies the pathogenesis of osteoporosis, the most common skeletal disease. Bone formation is linked to resorption through coupling factors, and this coupling limits the effectiveness of current therapies for the treatment of osteoporosis. Antiresorptives targeting osteoclasts can induce a decrease in osteoblast activity, and the ability of the parathyroid hormone agonist teriparatide to promote bone formation is partially counterbalanced by increased osteoclast resorptive activity [4, 5]. Identification of molecules that simultaneously enhance bone formation and suppress bone resorption is eagerly awaited

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