Research ArticleTENDON

Load-induced regulation of tendon homeostasis by SPARC, a genetic predisposition factor for tendon and ligament injuries

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Science Translational Medicine  24 Feb 2021:
Vol. 13, Issue 582, eabe5738
DOI: 10.1126/scitranslmed.abe5738

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Matrix maturation and mechanosensing

Tendons are important for mechanical load sensing and joint movement. Wang et al. studied the role of the matricellular protein SPARC in tendon loading, structure, and function. Mice lacking Sparc developed hypoplastic tendons, showed reduced maximal tensile stress at tendon-to-bone insertions, and were more prone to Achilles tendon ruptures after treadmill running as compared to wild-type mice. The authors determined that Sparc−/− tendon fascicles were more sensitive to mechanical load and identified a mutation in SPARC in patients with rotator cuff tendon tears that impaired collagen maturation, uncovering a potential mechanism by which SPARC mediates mechanical loading in tendon homeostasis.

Abstract

Tendons and tendon interfaces have a very limited regenerative capacity, rendering their injuries clinically challenging to resolve. Tendons sense muscle-mediated load; however, our knowledge on how loading affects tendon structure and functional adaption remains fragmentary. Here, we provide evidence that the matricellular protein secreted protein acidic and rich in cysteine (SPARC) is critically involved in the mechanobiology of tendons and is required for tissue maturation, homeostasis, and enthesis development. We show that tendon loading at the early postnatal stage leads to tissue hypotrophy and impaired maturation of Achilles tendon enthesis in Sparc−/− mice. Treadmill training revealed a higher prevalence of spontaneous tendon ruptures and a net catabolic adaptation in Sparc−/− mice. Tendon hypoplasia was attenuated in Sparc−/− mice in response to muscle unloading with botulinum toxin A. In vitro culture of Sparc−/− three-dimensional tendon constructs showed load-dependent impairment of ribosomal S6 kinase activation, resulting in reduced type I collagen synthesis. Further, functional calcium imaging revealed that lower stresses were required to trigger mechanically induced responses in Sparc−/− tendon fascicles. To underscore the clinical relevance of the findings, we further demonstrate that a missense mutation (p.Cys130Gln) in the follistatin-like domain of SPARC, which causes impaired protein secretion and type I collagen fibrillogenesis, is associated with tendon and ligament injuries in patients. Together, our results demonstrate that SPARC is a key extracellular matrix protein essential for load-induced tendon tissue maturation and homeostasis.

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