RRC ID 69873
Author Yoshida G, Kawabata T, Takamatsu H, Saita S, Nakamura S, Nishikawa K, Fujiwara M, Enokidani Y, Yamamuro T, Tabata K, Hamasaki M, Ishii M, Kumanogoh A, Yoshimori T.
Title Degradation of the NOTCH intracellular domain by elevated autophagy in osteoblasts promotes osteoblast differentiation and alleviates osteoporosis.
Journal Autophagy
Abstract Maintenance of bone integrity is mediated by the balanced actions of osteoblasts and osteoclasts. Because macroautophagy/autophagy regulates osteoblast mineralization, osteoclast differentiation, and their secretion from osteoclast cells, autophagy deficiency in osteoblasts or osteoclasts can disrupt this balance. However, it remains unclear whether upregulation of autophagy becomes beneficial for suppression of bone-associated diseases. In this study, we found that genetic upregulation of autophagy in osteoblasts facilitated bone formation. We generated mice in which autophagy was specifically upregulated in osteoblasts by deleting the gene encoding RUBCN/Rubicon, a negative regulator of autophagy. The rubcnflox/flox;Sp7/Osterix-Cre mice showed progressive skeletal abnormalities in femur bones. Consistent with this, RUBCN deficiency in osteoblasts resulted in elevated differentiation and mineralization, as well as an increase in the elevated expression of key transcription factors involved in osteoblast function such as Runx2 and Bglap/Osteocalcin. Furthermore, RUBCN deficiency in osteoblasts accelerated autophagic degradation of NOTCH intracellular domain (NICD) and downregulated the NOTCH signaling pathway, which negatively regulates osteoblast differentiation. Notably, osteoblast-specific deletion of RUBCN alleviated the phenotype in a mouse model of osteoporosis. We conclude that RUBCN is a key regulator of bone homeostasis. On the basis of these findings, we propose that medications targeting RUBCN or autophagic degradation of NICD could be used to treat age-related osteoporosis and bone fracture.Abbreviations: ALPL: alkaline phosphatase, liver/bone/kidney; BCIP/NBT: 5-bromo-4-chloro-3'-indolyl phosphate/nitro blue tetrazolium; BMD: bone mineral density; BV/TV: bone volume/total bone volume; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; NICD: NOTCH intracellular domain; RB1CC1/FIP200: RB1-inducible coiled-coil 1; RUBCN/Rubicon: RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein; SERM: selective estrogen receptor modulator; TNFRSF11B/OCIF: tumor necrosis factor receptor superfamily, member 11b (osteoprotegerin).
Volume 18(10)
Pages 2323-2332
Published 2022-10-1
DOI 10.1080/15548627.2021.2017587
PMID 35025696
PMC PMC9542956
MeSH Alkaline Phosphatase / metabolism Animals Autophagy / physiology Beclin-1 / metabolism Cell Differentiation Core Binding Factor Alpha 1 Subunit / metabolism Cysteine / metabolism Mice Microtubule-Associated Proteins / metabolism Osteoblasts / pathology Osteocalcin / metabolism Osteogenesis* Osteoporosis* / metabolism Osteoporosis* / pathology Osteoprotegerin / metabolism Phosphates / metabolism Receptors, Notch Selective Estrogen Receptor Modulators / metabolism Sirolimus TOR Serine-Threonine Kinases / metabolism
IF 9.77
Human and Animal Cells MC3T3-E1(RCB1126)