Musculoskeletal regeneration and its implications for the treatment of tendinopathy

Abstract

SUMMARYTendinopathies are common muskoloskeletal injuries that lead to pain and disability. Development and pathogenesis of tendinopathy is attributed to progressive pathological changes to the structure, function, and biology of tendon. The nature of this disease state, whether acquired by acute or chronic injury, is being actively investigated. Scarring, disorganized tissue, and loss of function characterize adult tendon healing. Recent work from animal models has begun to reveal the potential for adult mammalian tendon regeneration, the replacement of diseased with innate tissue. This review discusses what is known about musculoskeletal regeneration from a molecular perspective and how these findings can be applied to tendinopathy. Non-mammalian and mammalian models are discussed with emphasis on the potential of Murphy Roths Large mice to serve as a model of adult tendon regeneration. Comparison of regeneration in non-mammals, foetal mammals and adult mammals emphasizes distinctly different contributing factors to effective regeneration.

Uncorrelated healing response of tendon and ear injuries in MRL highlight a role for the local tendon environment in driving scarless healing

“…Consistent with findings from tendon laceration studies (10), MRL/MpJ tendons exhibited a significantly larger area of aligned ECM (1 week, P = 0.0164; 4 weeks, P < 0.0001; Figure 6A), and a significantly smaller area of unaligned ECM (1 week, P = 0.0281; 4 weeks, P < 0.0001; Figure 6B) compared to C57Bl/6 tendons at both 1 and 4 weeks. Cells in MRL/MpJ matrix demonstrated significantly lower variation in alignment at 1 week and 4 weeks in both highly aligned and unaligned matrix compared to cells in C57Bl/6 matrix (1 week aligned, P < 0.0001; 4 weeks aligned, P < 0.0001; 1 week unaligned, P < 0.0001; 4 weeks unaligned, P < 0.0001; Figure 6C–D).…”

“…This improved alignment is consistent with the enhanced tendon healing noted in other studies and insinuates that the provisional ECM of MRL/MpJ tendons harnesses unique structural cues that drive scarless tendon healing (10,25). In-vitro studies have also noted the benefit of proper matrix alignment on cell behavior, with increased alignment of cells in culture leading to improved cell morphology, matrix deposition and tenogenic marker expression over time (26,27).…”

“…Furthermore, very weak correlations were found between extent of healing in articular cartilage and closure of ear punch injury despite their shared systemic environment (5). Recently, Sereysky et al examined the healing capacity of tendons from MRL/MpJ in response to both acute injury, which exhibits the typical systemic inflammatory cascade, and sub-rupture fatigue injury, which is largely characterized by a biological response that is intrinsic to the tendon (10). Interestingly, the improved healing capacity of these mice extended to both types of injuries, as exhibited by restoration of structural and mechanical integrity, providing evidence that implicates the tissue’s local environment as a driver of the improved healing response.…”

Novel Model of Tendon Regeneration Reveals Distinct Cell Mechanisms Underlying Regenerative and Fibrotic Tendon Healing

“…This is in marked contrast with adult tendons, which remain functionally impaired after injury, consistent with numerous studies in the literature4950515253. Since function is the gold standard by which tendon healing is frequently assessed, our finding of improved neonatal tendon function is exciting and comparable to other existing regenerative tendon models, such as MRL/MpJ (and related mouse strains) and fetal sheep, which also recover functional properties after injury5455565758. Although MRL/MpJ and related strains are useful models of adult regeneration in specific contexts, a few recent studies in non-tendon tissues suggest that MRL/MpJ may exhibit accelerated wound closure via excessive scar formation rather than true regeneration59606162.…”

A Framework for Exercise Prescription

“…13 However, if the sarcolemma is intact, muscle cells may regenerate and the muscle should regain normal or near-normal function. If the basement membrane is damaged, regeneration cannot occur and repair happens primarily through scar tissue fi lling of the gaps.…”