TY - JOUR
T1 - NUMB maintains bone mass by promoting degradation of PTEN and GLI1 via ubiquitination in osteoblasts
AU - Ye, Ling
AU - Lou, Feng
AU - Yu, Fanyuan
AU - Zhang, Demao
AU - Wang, Chenglin
AU - Wu, Fanzi
AU - Li, Xin
AU - Ping, Yilin
AU - Yang, Xiao
AU - Yang, Jing
AU - Chen, Dian
AU - Gao, Bo
AU - Huang, Dingming
AU - Liu, Peng
N1 - Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85056284422
U2 - 10.1038/s41413-018-0030-y
DO - 10.1038/s41413-018-0030-y
M3 - Article
AN - SCOPUS:85056284422
SN - 2095-4700
VL - 6
JO - Bone Research
JF - Bone Research
IS - 1
M1 - 32
ER -