Rb1 negatively regulates bone formation and remodeling through inhibiting transcriptional regulation of YAP in Glut1 and OPG expression and glucose metabolism in male mice

Bone is a highly dynamic organ that undergoes constant bone formation and remodeling, and glucose as a major nutrient is necessary for bone formation and remodeling. Retinoblastoma (Rb1) is a critical regulator of mesenchymal stem cells (MSCs) fate, but how Rb1 regulates bone formation and remodelin...

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Bibliographic Details
Published in:Molecular metabolism (Germany) 2022-12, Vol.66, p.101630, Article 101630
Main Authors: Li, Yang, Yang, Shuting, Yang, Shuying
Format: Article
Language:English
Subjects:
Animals
Bone formation
Bone remodeling
Glucose - metabolism
Male
Mesenchymal Stem Cells - metabolism
Mice
MSCs
Original
Osteogenesis - physiology
Rb1
Retinal Neoplasms - metabolism
Retinoblastoma - metabolism
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Summary:Bone is a highly dynamic organ that undergoes constant bone formation and remodeling, and glucose as a major nutrient is necessary for bone formation and remodeling. Retinoblastoma (Rb1) is a critical regulator of mesenchymal stem cells (MSCs) fate, but how Rb1 regulates bone formation and remodeling is poorly understood. We generated MSCs- and osteoprogenitors-specific Rb1 knockout mouse models and utilized these models to explore the function and mechanism of Rb1 in regulating bone formation and remodeling in vivo and in vitro primary cell culture. Rb1 deficiency in MSCs significantly increased bone mass and impaired osteoclastogenesis. Consistently, depletion of Rb1 in osteoprogenitors significantly promoted bone formation. Mechanistically, loss of Rb1 in MSCs elevated YAP nuclear translocation and transcriptional activity of YAP/TEAD1 complex, thereby increasing the transcriptional expression of Glut1 and OPG. Moreover Prx1-Cre; Rb1f/f mice displayed hypoglycemia with increased systemic glucose tolerance instead of increased insulin level. In vitro data revealed that Rb1-mutant MSCs enhanced glucose uptake and lactate and ATP production. Increased osteogenesis caused by increased glucose metabolism and decreased osteoclastogenesis caused by increased expression of OPG eventually resulted in increased bone formation and remodeling. Collectively, these findings demonstrated that Rb1 in MSCs inhibits YAP-medicated Glut1 and OPG expression to control glucose metabolism, osteogenesis and osteoclastogenesis during bone formation and remodeling, which provide new insights that controlling Rb1 signaling may be a potential strategy for osteopetrosis. •Rb1 deficiency in MSCs increased bone mass and impaired osteoclastogenesis.•Rb1 deficiency in MSCs promoted osteogenesis and glucose metabolism by activating YAP signaling.•Prx1-Cre; Rb1f/f mice displayed hypoglycemia and increased systemic glucose tolerance instead of increased insulin level.•Rb1 deficiency in MSCs prohibited osteoclastogenesis through upregulation of OPG expression caused by YAP activation.
ISSN:2212-8778
2212-8778
DOI:10.1016/j.molmet.2022.101630