Department of Surgery, Division of Orthopaedics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Nat Commun. 2024 Apr 5;15(1):2956. doi: 10.1038/s41467-024-47413-2.
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.
SOXC（SOX4、SOX11 和 SOX12）转录因子先前被证明可以控制许多发育过程，包括骨骼发生，SOX4 与骨质疏松症有关，但 SOXC 如何控制成人骨量仍不清楚。在这里，我们使用 SOXC 缺失和功能获得的小鼠模型表明，SOXC 冗余地促进青春期前皮质骨量的增强，而只有 SOX4 减轻成年后早期和随后的小梁骨量的积累。SOX4 通过降低成骨细胞生成和增加破骨细胞生成来促进骨吸收而不是骨形成。单细胞转录组学揭示了其在 Lepr 间充质细胞中的普遍表达及其上调主要抗成骨细胞生成和促破骨细胞生成因子的能力，包括干扰素信号相关趋化因子，有助于这些成年干细胞的分泌组。因此，SOXC（主要是 SOX4）是成人骨量的关键调节因子。
