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.

Kelch 重复序列和 BTB （POZ） 结构域含结构域 2 （KBTBD2） 因其在代谢调节中的关键作用而闻名，尤其是在脂肪细胞中。然而，它在骨骼发育中的重要性仍然难以捉摸。在这里，我们揭示了 KBTBD2 在骨形成中以前未被认识的功能。胚胎骨软骨形成细胞或成骨细胞中 Kbtbd2 的条件敲除导致成骨分化受损，导致骨骼生长和矿化减少。从机制上讲，成骨过程中 KBTBD2 的丢失导致 p85α 的积累，p85α 是一种由磷酸肌醇-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 激活发挥有效的抑制作用。此外，我们的研究将对 KBTBD2 相关性的理解从骨骼生物学扩展到 SHORT 综合征的背景，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，携带 p.（Arg649Trp） 突变的 p85α 最常见于 SHORT 综合征患者，与 KBTBD2 的结合降低，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是必不可少的，并表明 KBTBD2 介导的 p85α 调节的缺失是 SHORT 综合征的潜在机制。