The mechanisms underlying tendon development are by far the least understood of any component of the musculoskeletal system. This is a concern because tendon injuries are common and treatment options are limited. Healing often results in formation of scar tissue, which is compositionally and mechanically inferior to native tendon, resulting in decreased flexibility and a high recurrent tear rate. Members of the CCN family of matricellular proteins have been extensively studied due to their key roles in multiple fibrotic conditions, but their roles in normal fibrous tissues like tendons are unknown. We found that CCN1/Cyr61 s highly expressed in tendon and ligament, and that mice in which Ccn1 is ablated in tendon/ligament progenitor stem cells (TPSCs) using Scx-Cre (Ccn1SKO) exhibit a clubfoot-like phenotype. Histological analysis revealed that anterior cruciate ligament (ACL), Achilles and patellar tendons are substantially thicker and more stout than in wild-type (WT) littermates at birth; these defects persist in adults. The affected tendon displays stronger mechanical properties early, but becomes significantly weaker with age. No other mutants with a similar phenotype have been described to date. Initial RNA-Seq and phenotypic analysis revealed that affected tendons in Ccn1SKO mice acquire a gene expression profile similar to that of activated wound fibroblasts. We therefore have a unique opportunity to identify new mechanisms regulating tendon formation and remodeling that have direct therapeutic potential. We plan to: 1) define the function of CCN1/Cyr61 in tendon formation and maintenance in vivo through phenotypic analysis of Ccn1SKO mice, and 2) test the hypothesis that CCN1/Cyr61 is required in TPSCs/tenocytes to promote the tenogenic phenotype and prevent acquisition of an activated wound fibroblast fate. Success with these studies would provide a strong rationale for future studies that evaluate the function of CCN1/Cyr61 in tendon injury/repair and develop CCN1/Cyr61 as a therapeutic agent to promote scarless tendon healing.

Public Health Relevance

Tendon healing often results in scar tissue, leading to decreased flexibility and recurrent tears. We discovered that the secreted protein CCN1/Cyr61 is required for tendon development, and its loss causes tendon cells to resemble cells found in scar tissue. We plan to test whether CCN1/CYr61 is required to prevent tendon cells from converting into scar-forming fibroblasts with the expectation that these will studies will lead to future studies testing whether CCN1/Cyr61 can be used therapeutically to promote scar-free tendon healing.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Exploratory/Developmental Grants (R21)
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Skeletal Biology Structure and Regeneration Study Section (SBSR)
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Washabaugh, Charles H
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Zhao, Gexin; Huang, Bau-Lin; Rigueur, Diana et al. (2018) CYR61/CCN1 Regulates Sclerostin Levels and Bone Maintenance. J Bone Miner Res 33:1076-1089