The adaptor protein NUMB is involved in asymmetric division and cell fate determination and recognized as an antagonist of Notch. Previous studies have proved that Notch activation in osteoblasts contributes to a high bone mass. In this study, however, an osteopenic phenotype was found in 9-week-old mice using osteoblastic specific Col1a1–2.3-Cre to ablate both Numb and its homologue Numbl . The trabecular bone mass decreased dramatically while the cortical bone mass was unaffected. Here, the Notch signal was not activated, while the tensin homologue deleted on human chromosome 10 (PTEN), which dephosphorylates phosphatidylinositide 3-kinases, was elevated, attenuating protein kinase B (Akt). The ubiquitination assay revealed that NUMB may physiologically promote PTEN ubiquitination in the presence of neural precursor cell-expressed developmentally downregulated protein 4–1. In addition, the deficiency of Numb/Numbl also activated the Hedgehog pathway through GLI1. This process was found to improve the ratio of the receptor activator of nuclear factor-kB ligand to osteoprotegerin, which enhanced the differentiation of osteoclasts and bone resorption . In conclusion, this study provides an insight into new functons of NUMB and NUMBL on bone homeostasis.

衔接蛋白NUMB参与不对称分裂和细胞命运的确定，并被认为是Notch的拮抗剂。先前的研究已经证明，成骨细胞中的Notch活化有助于增加骨量。但是，在这项研究中，使用成骨细胞特异性Col1a1–2.3-Cre消融了Numb及其同系物Numbl的9周龄小鼠中发现了骨质减少的表型 。小梁骨量显着减少，而皮质骨量不受影响。在这里，Notch信号没有被激活，而在人类10号染色体（PTEN）上缺失的张力蛋白同源物却升高了，从而使磷脂酰肌醇3激酶去磷酸化，从而减弱了蛋白激酶B（Akt）。泛素化测定显示，在存在神经前体细胞表达的发育下调的蛋白4-1存在下，NUMB可能在生理上促进PTEN泛素化。另外，Numb / Numbl的不足还通过GLI1激活了刺猬通路。发现该过程改善了核因子-kB配体的受体活化剂与骨保护素的比例，从而增强了破骨细胞的分化和骨吸收。总之，本研究提供了有关NUMB和NUMBL在骨稳态中新功能的见解。