Oral Presentation 1st Asia Pacific Herbert Fleisch Workshop 2025

Cbfβ in vascular smooth muscle cells as a key regulator of bone and vascular homeostasis (#24)

Xian Jin 1 , Xiangguo Che 1 , Dong-Kyo Lee 1 , Poo-Reum Choi 1 , Ying Cui 1 , Hyun-Ju Kim 1 , Je-Yong Choi 1
  1. Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, South Korea

Objectives

Vasculogenesis plays an essential role in bone development. Cbfβ, a ubiquitously expressed cytoplasmic partner protein of Runx transcription factors, is critical for definitive hematopoiesis. However, the role of Cbfβ in vascular smooth muscle cells (VSMCs) and its impact on bone and vascular homeostasis remains unclear. This study investigated the effects of Cbfβ in VSMCs on vascular integrity and bone metabolic homeostasis.

 

Methods

To generate VSMC-specific Cbfβ KO mice, we crossed Sm22α-Cre with Cbfβfl/fl mice, creating Sm22α-Cre; Cbfβfl/fl (Cbfβ△vc/△vc) mice. We analyzed the vessel and bone phenotypes by histology, immunohistochemistry, serum biochemistry, micro-CT analysis, 3-point bending test, and dynamic bone histomorphometry. For molecular mechanism studies, we used primary cultured VSMCs and mouse vascular smooth muscle (MOVAS) cell lines to determine the effects of VSMC-derived factors on bone cell activity and differentiation.

 

Results

Cbfβ△vc/△vc mice showed increased vascular smooth muscle thickness, elevated blood pressure, and enhanced VSMC proliferation in the aorta. These mice exhibited delayed endochondral ossification and skull mineralization during development. Analysis of adult skeletal tissue revealed increased osteoclast numbers and reduced bone mass, and decreased bone strength in 20-week-old mice compared to wild-type (WT) mice. Serum biochemical analysis demonstrated normal calcium, phosphate, and OPG levels but increased serum CTX and RANKL levels in Cbfβ△vc/△vc mice compared to WT. In vitro mechanistic studies demonstrated that conditioned medium derived from Cbfβ△vc/△vc VSMCs showed a higher RANKL/OPG ratio due to lower OPG and higher RANKL levels, leading to increased osteoclast differentiation and upregulation of osteoclastogenic markers compared to the control.

 

Conclusions

Our findings unveil a novel role of Cbfβ in VSMCs in regulating bone and vascular homeostasis, suggesting the existence of a vascular and bone axis. This study significantly enhances our understanding of the relationship between vasculature and bone metabolism.