Whitening of brown adipose tissue inhibits osteogenic differentiation via secretion of S100A8/A9

• DOI: 10.1016/j.isci.2024.108857
• Publication Date: 2024-01-11T09:49:15Z
• Authors: Ting Wang; Chaoran Zhao; Jiahuan Zhang; Shengfa Li; Youming Zhang; Yan Gong; Yingyue Zhou; Lei Yan; Sheng Zhang; Zhongmin Zhang; Hongling Hu; Anling Liu; Xiaochun Bai; Zhipeng Zou
• Keywords: 0301 basic medicine; Cell biology; 03 medical and health sciences; Physiology; Molecular biology; Science; Q; Article

The mechanism by which brown adipose tissue (BAT) regulates bone metabolism is unclear. Here, we reveal that BAT secretes S100A8/A9, a previously unidentified BAT adipokine (batokine), to impair bone formation. Brown adipocytes-specific knockout of Rheb (RhebBAD KO), the upstream activator of mTOR, causes BAT malfunction to inhibit osteogenesis. Rheb depletion induces NF-κB dependent S100A8/A9 secretion from brown adipocytes, but not from macrophages. In wild-type mice, age-related Rheb downregulation in BAT is associated with enhanced S100A8/A9 secretion. Either batokines from RhebBAD KO mice, or recombinant S100A8/A9, inhibits osteoblast differentiation of mesenchymal stem cells in vitro by targeting toll-like receptor 4 on their surfaces. Conversely, S100A8/A9 neutralization not only rescues the osteogenesis repressed in the RhebBAD KO mice, but also alleviates age-related osteoporosis in wild-type mice. Collectively, our data revealed an unexpected BAT-bone crosstalk driven by Rheb-S100A8/A9, uncovering S100A8/A9 as a promising target for the treatment, and potentially, prevention of osteoporosis.