Center for Biotherapy, Eighth Affiliated Hospital of Sun Yat-Sen University, Shenzhen, People's Republic of China.
Department of Orthopedics, Eighth Affiliated Hospital of Sun Yat-Sen University, Shenzhen, People's Republic of China.
Stem Cells. 2022 May 27;40(5):508-522. doi: 10.1093/stmcls/sxac013.
Bone marrow (BM) adipose tissue (BMAT), a unique adipose depot, plays an important role in diseases such as osteoporosis and bone metastasis. Precise control of mesenchymal stem cell (MSC) differentiation is critical for BMAT formation and regeneration. Here, we show that death associated protein kinase 1 (DAPK1) negatively regulates BM adipogenesis in vitro and in vivo. Prx1creDapk1loxp/loxp mice showed more adipocytes in the femur than Dapk1loxp/loxp mice. Further mechanistic analyses revealed that DAPK1 inhibits p38 mitogen-activated protein kinase (MAPK) signaling in the nucleus by binding the p38 isoform MAPK14, decreasing p38 nuclear activity, which subsequently inhibits BM adipogenesis. The inhibitory effect of DAPK1 against MAPK14 was independent of its kinase activity. In addition, the decreased DAPK1 was observed in the BM-MSCs of ageing mice. Our results reveal a previously undescribed function for DAPK1 in the regulation of adipogenesis and may also reveal the underlying mechanism of BMAT formation in ageing.
骨髓（BM）脂肪组织（BMAT）是一种独特的脂肪组织，在骨质疏松症和骨转移等疾病中发挥着重要作用。精确控制间充质干细胞（MSC）分化对于 BMAT 的形成和再生至关重要。在这里，我们表明凋亡相关蛋白激酶 1（DAPK1）在体外和体内负调控 BM 脂肪生成。Prx1creDapk1loxp/loxp 小鼠的股骨中脂肪细胞比 Dapk1loxp/loxp 小鼠多。进一步的机制分析表明，DAPK1 通过与 p38 同工型 MAPK14 结合，抑制核内 p38 有丝分裂原激活的蛋白激酶（MAPK）信号，从而减少 p38 核活性，进而抑制 BM 脂肪生成。DAPK1 对 MAPK14 的抑制作用与其激酶活性无关。此外，在衰老小鼠的 BM-MSCs 中观察到 DAPK1 减少。我们的研究结果揭示了 DAPK1 在调节脂肪生成中的一个先前未被描述的功能，也可能揭示了衰老过程中 BMAT 形成的潜在机制。
