Role and underlying mechanisms of integrin α2β1 related cell-matrix interaction in tendon homeostasis and age related degradation

• Applicant: Professor Dr. Richard Stange
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 500341476

Aging affects multiple aspects of the anatomy and physiology including the tendons, which connect muscles to bones. It lowers metabolic activity of tendons as well as tissue regenerative potential. Age related structural changes in tendons such as decrease in collagen content reduces mechanical properties of tendons and predisposes them to injury. Tendinopathy thereby describes a complex multifaceted pathology of the tendon, clinically characterized by activity-related tendon pain, decline in function and restricted mobility and disability, finally prone to tendon ruptures altogether leading to a high socio-economic burden. Tendon tissue shows low cellularity and most of the dry mass of the tendon consists of collagen fibrils, with collagen type I as main component. Collagen fibrils are important for tendon tensile strength, whereas other extracellular matrix proteins like proteoglycans can bind large quantities of water, providing protection against compressive forces and contribution to the overall flexibility of the material. We could recently demonstrate that the absence of integrin α2β1, one of the major collagen receptors, is detrimental to overall tendon biomechanical stability. In integrin α2β1 deficient tendons, we could observe an increased matrix turnover as well as reduction of the presence of proteoglycans. This points out to an important role of integrin α2β1 in tendon homeostasis and regeneration. We could link the increased generation of extracellular matrix with a higher expression of BMP-2, which is capable to induce collagen expression in tendon cells. However the degenerative part is still unclear, yet. The proposed translational research project aims to elucidate and characterize in detail the role and underlying mechanisms of integrin α2β1 in tendon homeostasis and age related degradation linking to further tendinopathies that occur in human patients. In vitro, we will analyze if the misbalance in collagen-associated proteins is the cause of inferior tendon quality in integrin α2β1 deficient tendons. In vivo we will characterize stability and structure of murine extracellular matrix and tendon quality under physiological and age-related degenerative conditions in wild type and integrin α2 deficient animals. In a translational approach, we will collect tissue, isolate primary tenocytes and analyze blood samples from patients with tendinopathies to investigate if integrin α2 and its linked phenotype is associated with increased tendon pathology and further elucidate the predictive value of collagen-binding integrins for tendinopathy development.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Michael J. Raschke