Xun Yu, Jiang Yiao, Khalid Aysha, Tian Zeru, Rios Jonathan, Zhang Zhao
Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Division of Endocrinology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Cell Death Differ. 2024 Nov 19. doi: 10.1038/s41418-024-01416-0.
Kelch repeat and BTB (POZ) domain-containing 2 (KBTBD2) is known for its pivotal role in metabolic regulation, particularly in adipocytes. However, its significance in skeletal development has remained elusive. Here, we uncover a previously unrecognized function of KBTBD2 in bone formation. Conditional knockout of Kbtbd2 in embryonic osteochondroprogenitor cells or osteoblasts results in impaired osteogenic differentiation, leading to reduced skeletal growth and mineralization. Mechanistically, the loss of KBTBD2 during osteogenesis leads to the accumulation of p85α, a regulatory subunit encoded by phosphoinositide-3-kinase regulatory subunit 1 (Pik3r1), which exerts a potent inhibitory effect on insulin-like growth factor 1 (IGF-1)-induced activation of AKT. Moreover, our study extends the understanding of KBTBD2's relevance beyond bone biology to the context of SHORT syndrome, a rare genetic disorder marked by short stature and various physical abnormalities. We demonstrate that p85α harboring the p.(Arg649Trp) mutation, most frequently found in SHORT syndrome patients, exhibits reduced binding to KBTBD2, leading to impaired IGF-1-mediated activation of AKT. These findings reveal that KBTBD2 is essential in bone formation via regulating the IGF-1 signaling pathway and suggest loss of KBTBD2-mediated regulation of p85α as a potential mechanism for SHORT syndrome.
含 Kelch 重复序列和 BTB（POZ）结构域蛋白 2（KBTBD2）以其在代谢调节尤其是脂肪细胞中的关键作用而闻名。然而，其在骨骼发育中的意义仍不明确。在此，我们发现了 KBTBD2 在骨形成中一个此前未被认识到的功能。在胚胎骨软骨祖细胞或成骨细胞中条件性敲除 Kbtbd2 会导致成骨分化受损，进而导致骨骼生长和矿化减少。从机制上讲，在骨生成过程中 KBTBD2 的缺失会导致 p85α 的积累，p85α 是由磷酸肌醇 -3-激酶调节亚基 1（Pik3r1）编码的调节亚基，它对胰岛素样生长因子 1（IGF-1）诱导的 AKT 激活具有强大的抑制作用。此外，我们的研究将对 KBTBD2 相关性的理解从骨生物学扩展到了 SHORT 综合征的背景下，SHORT 综合征是一种以身材矮小和各种身体异常为特征的罕见遗传疾病。我们证明，在 SHORT 综合征患者中最常见的携带 p.(Arg649Trp) 突变的 p85α 与 KBTBD2 的结合减少，导致 IGF-1 介导的 AKT 激活受损。这些发现揭示了 KBTBD2 通过调节 IGF-1 信号通路在骨形成中至关重要，并表明 KBTBD2 介导的 p85α 调节缺失是 SHORT 综合征的一种潜在机制。
