Musculoskeletal regeneration and its implications for the treatment of tendinopathy

Abstract

Tendinopathies 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.

Keywords: C57BL/6J; MRL; MRL/MpJ; healing; regeneration; scar-mediated; scarless; tendon.

Figure 1

H&E stain micrographs of normal adult tendon (a, 50× magnification) and normal fetal tendon (b, 400× magnification). Injured adult tendon (c) retains disruption of the collagen fibers at the site of India ink marking (arrow) and the disruption of normal collagen organization and disorganized granulation tissue at the site of wounding (asterisk). Injured fetal tendon (d) remodels, revealing no structural abnormalities or lack of collagen fiber disorganization at the wound site (identified with charcoal, arrow). The collagen architecture appears to be completely restored (adapted from Beredjiklian et al. 2003).

Figure 2

Through-and-through 2 mm holes are punched in the middle of the ear pinnae, clearly seen at day 0 in both C57BL/6J (a) and MRL/MpJ (b). By day 30, however, earholes remain clearly seen in C57BL/6J (c) but have been replaced by native tissue in MRL/MpJ (d), denoting regeneration (Adapted from Clark et al. 1998).

Figure 3

TGF-β presence (brown, positive staining, arrows) post-laceration in C57BL/6J control (a), week 4 (b), and week 8 (c), and in MRL/MpJ control (d), week 4 (e), and week 8 (f), revealing higher levels in MRL/MpJ at all timepoints (adapted from Sereysky et al. 2013).

Figure 4

MMP-2 presence (brown, positive staining, arrows) post-laceration in C57BL/6J control (a), week 4 (b), and week 8 (c), and in MRL/MpJ control (d), week 4 (e), and week 8 (f), revealing higher levels in MRL/MpJ at all timepoints (adapted from Sereysky et al. 2013).

Figure 5

Toluidine Blue stain for proteoglycan content (degree of blue color) post-laceration in C57BL/6J control (a), week 4 (b), and week 8 (c), and in MRL/MpJ control (f), week 4 (g), and week 8 (h), revealing high levels in C57BL/6J through week 8, while MRL/MpJ returned to naïve between weeks 4 and 8. Picrosirius red stain for collagen maturity and organization (degree of red color) post-laceration in C57Bl/6J control (d), and week 8 (e), and in MRL/MpJ control (i) and week 8 (j), revealing restoration of naïve collagen structure in MRL/MpJ at week 8 (adapted from Sereysky et al. 2013).

Figure 6

Stiffness of sub-rupture fatigue injured tendon, normalized by contralateral tendon. C57BL/6J does not recover naïve function by week 8 post-injury (a). MRL/MpJ recovers naïve function between weeks 4 and 8 post-injury (b) (adapted from Sereysky et al. 2013).