Research Centre, Shriners Hospital for Children-Canada, Montreal, Canada.
Department of Human Genetics, Faculty of Medicine and Health Sciences, McGill University, Montreal, Canada.
J Bone Miner Res. 2023 Apr;38(4):578-596. doi: 10.1002/jbmr.4778. Epub 2023 Feb 9.
In the skeleton, osteoblasts and osteoclasts synchronize their activities to maintain bone homeostasis and integrity. Investigating the molecular mechanisms governing bone remodeling is critical and helps understand the underlying biology of bone disorders. Initially, we have identified the ubiquitin-specific peptidase gene (Usp53) as a target of the parathyroid hormone in osteoblasts and a regulator of mesenchymal stem cell differentiation. Mutations in USP53 have been linked to a constellation of developmental pathologies. However, the role of Usp53 in bone has never been visited. Here we show that Usp53 null mice have a low bone mass phenotype in vivo. Usp53 null mice exhibit a pronounced decrease in trabecular bone indices including trabecular bone volume (36%) and trabecular number (26%) along with an increase in trabecular separation (13%). Cortical bone parameters are also impacted, showing a reduction in cortical bone volume (12%) and cortical bone thickness (15%). As a result, the strength and mechanical bone properties of Usp53 null mice have been compromised. At the cellular level, the ablation of Usp53 perturbs bone remodeling, augments osteoblast-dependent osteoclastogenesis, and increases osteoclast numbers. Bone marrow adipose tissue volume increased significantly with age in Usp53-deficient mice. Usp53 null mice displayed increased serum receptor activator of NF-κB ligand (RANKL) levels, and Usp53-deficient osteoblasts and bone marrow adipocytes have increased expression of Rankl. Mechanistically, USP53 regulates Rankl expression by enhancing the interaction between VDR and SMAD3. This is the first report describing the function of Usp53 during skeletal development. Our results put Usp53 in display as a novel regulator of osteoblast-osteoclast coupling and open the door for investigating the involvement of USP53 in pathologies. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
在骨骼中，成骨细胞和破骨细胞同步活动以维持骨稳态和完整性。研究调节骨重塑的分子机制至关重要，有助于了解骨疾病的基础生物学。最初，我们已经确定泛素特异性肽酶基因 (Usp53) 是成骨细胞中甲状旁腺激素的靶标和间充质干细胞分化的调节剂。USP53 突变与一系列发育病理学有关。然而，Usp53 在骨中的作用从未被研究过。在这里，我们显示 Usp53 缺失小鼠在体内表现出低骨量表型。Usp53 缺失小鼠表现出明显的骨小梁骨指数降低，包括骨小梁体积 (36%) 和骨小梁数量 (26%)，同时伴有骨小梁分离增加 (13%)。皮质骨参数也受到影响，表现为皮质骨体积减少 (12%) 和皮质骨厚度减少 (15%)。因此，Usp53 缺失小鼠的骨骼强度和机械特性受到了损害。在细胞水平上，Usp53 的缺失扰乱了骨重塑，增强了成骨细胞依赖性破骨细胞生成，并增加了破骨细胞数量。Usp53 缺陷小鼠的骨髓脂肪组织体积随年龄显著增加。Usp53 缺失小鼠的血清核因子 κB 受体激活剂配体 (RANKL) 水平升高，Usp53 缺陷成骨细胞和骨髓脂肪细胞中 Rankl 的表达增加。在机制上，USP53 通过增强 VDR 和 SMAD3 之间的相互作用来调节 Rankl 表达。这是首次描述 Usp53 在骨骼发育过程中的功能的报告。我们的结果表明 Usp53 是成骨细胞-破骨细胞偶联的新调节剂，并为研究 USP53 在病理学中的参与打开了大门。 © 2023 作者。骨与矿物质研究杂志由 Wiley 期刊出版公司代表美国骨与矿物质研究协会 (ASBMR) 出版。
