Increased Ca 2+ signaling through Ca V 1.2 induces tendon hypertrophy with increased collagen fibrillogenesis and biomechanical properties
Increased Ca 2+ signaling through Ca V 1.2 induces tendon hypertrophy with increased collagen fibrillogenesis and biomechanical properties
Abstract Tendons are tension-bearing tissues transmitting force from muscle to bone for body movement. This mechanical loading is essential for tendon development, homeostasis, and healing after injury. While Ca2+ signaling has been studied extensively for its roles in mechanotransduction, regulating muscle, bone and cartilage development and homeostasis, knowledge about Ca2+ signaling and the source of Ca2+ signals in tendon fibroblast biology are largely unknown. Here, we investigated the function of Ca2+ signaling through CaV1.2 voltage-gated Ca2+ channel in tendon formation. Using a reporter mouse, we found that CaV1.2 is highly expressed in tendon during development and downregulated in adult homeostasis. To assess its function, we generated ScxCre;CaV1.2TS mice that express a gain-of-function mutant CaV1.2 channel (CaV1.2TS) in tendon. We found that tendons in the mutant mice were approximately 2/3 larger and had more tendon fibroblasts, but the cell density of the mutant mice decreased by around 22%. TEM analyses demonstrated increased collagen fibrillogenesis in the hypertrophic tendon. Biomechanical testing revealed that the hypertrophic Achilles tendons display higher peak load and stiffness, with no changes in peak stress and elastic modulus. Proteomics analysis reveals no significant difference in the abundance of major extracellular matrix (ECM) type I and III collagens, but mutant mice had about 2-fold increase in other ECM proteins such as tenascin C, tenomodulin, periostin, type XIV and type VIII collagens, around 11-fold increase in the growth factor of TGF-β family myostatin, and significant elevation of matrix remodeling proteins including Mmp14, Mmp2 and cathepsin K. Taken together, these data highlight roles for increased Ca2+ signaling through CaV1.2 on regulating expression of myostatin growth factor and ECM proteins for tendon collagen fibrillogenesis during tendon formation.
Li Haiyin、Rodeo Scott A.、Loiselle Alayna E.、Cao Chike、Mendias Christopher L.、Pitt Geoffrey S.、Korcari Antonion、Ciufo David、Buckley Mark R.
Center for Musculoskeletal Research, University of Rochester Medical Center||Department of Orthopeadics, University of Rochester Medical CenterSports Medicine and Shoulder Service, Hospital for Special SurgeryCenter for Musculoskeletal Research, University of Rochester Medical Center||Department of Orthopeadics, University of Rochester Medical CenterCenter for Musculoskeletal Research, University of Rochester Medical Center||Department of Orthopeadics, University of Rochester Medical CenterArizona Bone, Joint and Sports Medicine CenterCardiovascular Research Institute, Weill Cornell MedicineCenter for Musculoskeletal Research, University of Rochester Medical Center||Department of Biomedical Engineering, University of Rochester Medical CenterCenter for Musculoskeletal Research, University of Rochester Medical Center||Department of Orthopeadics, University of Rochester Medical CenterCenter for Musculoskeletal Research, University of Rochester Medical Center||Department of Biomedical Engineering, University of Rochester Medical Center
基础医学生理学分子生物学
Li Haiyin,Rodeo Scott A.,Loiselle Alayna E.,Cao Chike,Mendias Christopher L.,Pitt Geoffrey S.,Korcari Antonion,Ciufo David,Buckley Mark R..Increased Ca 2+ signaling through Ca V 1.2 induces tendon hypertrophy with increased collagen fibrillogenesis and biomechanical properties[EB/OL].(2025-03-28)[2025-05-28].https://www.biorxiv.org/content/10.1101/2023.01.24.525119.点此复制
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