Targeting endothelial PDGFR‐β facilitates angiogenesis‐associated bone formation through the PAK1/NICD axis

• Published in: Journal of cellular physiology 2024-08, Vol.239 (8), p.e31291-n/a
• Main Authors: Lin, Hancheng, Lin, Rongmin, Hou, Jiahui, Zhu, Chencheng, Liu, Guanqiao, Lin, Yihuang, Su, Jianwen, Yang, Mankai, Yang, Bingsheng, Ma, Yuan, Cheng, Caiyu, Deng, Mingye, Yu, Bin, Xu, Ting, Wu, HangTian, Cui, Zhuang
• Format: Article
• Language: English
• Subjects: Angiogenesis; Blood vessels; Bone growth; Bone loss; Bone turnover; Endothelial cells; Endothelium; Growth factors; Homeostasis; H‐type vessels; Intracellular signalling; Kinases; NICD; Notch1 protein; Osteogenesis; Osteoporosis; Ovariectomy; PAK1; Pathogenesis; PDGFR‐β
• ISSN: 0021-9541; 1097-4652; 1097-4652
• DOI: 10.1002/jcp.31291

The intricate orchestration of osteoporosis (OP) pathogenesis remains elusive. Mounting evidence suggests that angiogenesis‐driven osteogenesis serves as a crucial foundation for maintaining bone homeostasis. This study aimed to explore the potential of the endothelial platelet‐derived growth factor receptor‐β (PDGFR‐β) in mitigating bone loss through its facilitation of H‐type vessel formation. Our findings demonstrate that the expression level of endothelial PDGFR‐β is reduced in samples obtained from individuals suffering from OP, as well as in ovariectomy mice. Depletion of PDGFR‐β in endothelial cells ameliorates angiogenesis‐mediated bone formation in mice. The regulatory influence of endothelial PDGFR‐β on H‐type vessels is mediated through the PDGFRβ‐P21‐activated kinase 1‐Notch1 intracellular domain signaling cascade. In particular, the endothelium‐specific enhancement of PDGFR‐β facilitates H‐type vessels and their associated bone formation in OP. Hence, the strategic targeting of endothelial PDGFR‐β emerges as a promising therapeutic approach for the management of OP in the near future. Endothelial PDGFR‐β plays a pivotal role in osteoporosis by modulating angiogenesis‐associated osteogenesis. Endothelial PDGFR‐β exerts regulatory control over H‐type vessel formation through the PDGFRβ‐PAK1‐NICD signaling cascade. Depletion of PDGFR‐β or interruption of PAK1/NICD axis in endothelial cells (ECs) ameliorates vessel formation and its mediated bone formation, while overexpression of PDGFR‐β reverses this phenomenon.