SOXC are critical regulators of adult bone mass

AUTHORS

Marco Angelozzi, Anirudha Karvande & Véronique Lefebvre

ABSTRACT

Pivotal in many ways for human health, the control of adult bone mass is governed by complex, incompletely understood crosstalk namely between mesenchymal stem cells, osteoblasts and osteoclasts. The SOX4, SOX11 and SOX12 (SOXC) transcription factors were previously shown to control many developmental processes, including skeletogenesis, and SOX4 was linked to osteoporosis, but how SOXC control adult bone mass remains unknown. Using SOXC loss- and gain-of-function mouse models, we show here that SOXC redundantly promote prepubertal cortical bone mass strengthening whereas only SOX4 mitigates adult trabecular bone mass accrual in early adulthood and subsequent maintenance. SOX4 favors bone resorption over formation by lowering osteoblastogenesis and increasing osteoclastogenesis. Single-cell transcriptomics reveals its prevalent expression in Lepr+ mesenchymal cells and ability to upregulate genes for prominent anti-osteoblastogenic and pro-osteoclastogenic factors, including interferon signaling-related chemokines, contributing to these adult stem cells’ secretome. SOXC, with SOX4 predominantly, are thus key regulators of adult bone mass.

Ano5 modulates calcium signaling during bone homeostasis in gnathodiaphyseal dysplasia

AUTHORS

Xin Li, Lei Wang, Hongwei Wang, An Qin & Xingjun Qin

ABSTRACT

ANO5 encodes transmembrane protein 16E (TMEM16E), an intracellular calcium-activated chloride channel in the endoplasmic reticulum. Mutations in ANO5 are associated with gnathodiaphyseal dysplasia (GDD), a skeletal disorder causing the jaw deformity and long bone fractures. However, the coordinated mechanism by which ANO5 mediates bone homeostasis in GDD remains poorly defined. Here, we show that ablation of Ano5 reduced intracellular calcium transients, leading to defects in osteogenesis and osteoclastogenesis and thus bone dysplasia. We found a causative de novo ANO5 frameshift insertion mutation (p.L370_A371insDYWRLNSTCL) in a GDD family with osteopenia, accompanied by a decrease in TMEM16E expression and impaired RANKL-induced intracellular calcium ([Ca2+]i) oscillations in osteoclasts. Moreover, using Ano5 knockout (KO) mice, we found that they exhibited low bone volume, abnormal calcium deposits, and defective osteoblast and osteoclast differentiation. We also showed that Ano5 deletion in mice significantly diminished [Ca2+]i oscillations in both osteoblasts and osteoclasts, which resulted in reduced WNT/β-Catenin and RANKL-NFATc1 signaling, respectively. Osteoanabolic treatment of parathyroid hormone was effective in enhancing bone strength in Ano5 KO mice. Consequently, these data demonstrate that Ano5 positively modulates bone homeostasis via calcium signaling in GDD.