Mechanical stress determines the configuration of TGF\u03b2 activation in articular cartilage

Gehua Zhen,Yusheng Li,Byoung Choul Kim,Qiaoyue Guo,Jessie Huang,Taekjip Ha,Yang Dan,X Edward Guo,Steven An,Ruomei Wang,Shouan Zhu,Chuanlong Wu,Yizhong Hu,Xu Cao,Mei Wan

doi:10.1038/s41467-021-21948-0

Abstract

Our incomplete understanding of osteoarthritis (OA) pathogenesis has significantly hindered the development of disease-modifying therapy. The functional relationship between subchondral bone (SB) and articular cartilage (AC) is unclear. Here, we found that the changes of SB architecture altered the distribution of mechanical stress on AC. Importantly, the latter is well aligned with the pattern of transforming growth factor beta (TGFβ) activity in AC, which is essential in the regulation of AC homeostasis. Specifically, TGFβ activity is concentrated in the areas of AC with high mechanical stress. A high level of TGFβ disrupts the cartilage homeostasis and impairs the metabolic activity of chondrocytes. Mechanical stress stimulates talin-centered cytoskeletal reorganization and the consequent increase of cell contractile forces and cell stiffness of chondrocytes, which triggers αV integrin–mediated TGFβ activation. Knockout of αV integrin in chondrocytes reversed the alteration of TGFβ activation and subsequent metabolic abnormalities in AC and attenuated cartilage degeneration in an OA mouse model. Thus, SB structure determines the patterns of mechanical stress and the configuration of TGFβ activation in AC, which subsequently regulates chondrocyte metabolism and AC homeostasis.

Highlights

Our incomplete understanding of osteoarthritis (OA) pathogenesis has significantly hindered the development of disease-modifying therapy
We found that uncoupled remodeling resulted in excessive transforming growth factor beta (TGFβ) activation, which induced the clustering of osteoprogenitors and angiogenesis in the bone marrow cavity and abnormal formation of subchondral bone (SB) at the onset of OA11
Because the contractile force exerted by the chondrocytes was relayed by the αV integrin–RGD bond, our result suggests that the αV integrin–RGD bond could bear a strong molecular tension >43 pN and even 54 pN in chondrocytes that are challenged by mechanical stress

Summary

Introduction

Our incomplete understanding of osteoarthritis (OA) pathogenesis has significantly hindered the development of disease-modifying therapy. We found that the changes of SB architecture altered the distribution of mechanical stress on AC The latter is well aligned with the pattern of transforming growth factor beta (TGFβ) activity in AC, which is essential in the regulation of AC homeostasis. Knockout of αV integrin in chondrocytes reversed the alteration of TGFβ activation and subsequent metabolic abnormalities in AC and attenuated cartilage degeneration in an OA mouse model. SB structure determines the patterns of mechanical stress and the configuration of TGFβ activation in AC, which subsequently regulates chondrocyte metabolism and AC homeostasis. We found that uncoupled remodeling resulted in excessive transforming growth factor beta (TGFβ) activation, which induced the clustering of osteoprogenitors and angiogenesis in the bone marrow cavity and abnormal formation of SB at the onset of OA11. We found that the incremental increase of either SB size or subchondral plate stiffness modulus results in a significant elevation of peak stress on the articular surface

Methods

Results

Conclusion