MicroRNA29a Treatment Improves Early Tendon Injury

Abstract

Tendon injuries (tendinopathies) are common in human and equine athletes and characterized by dysregulated collagen matrix, resulting in tendon damage. We have previously demonstrated a functional role for microRNA29a (miR29a) as a post-transcriptional regulator of collagen 3 expression in murine and human tendon injury. Given the translational potential, we designed a randomized, blinded trial to evaluate the potential of a miR29a replacement therapy as a therapeutic option to treat tendinopathy in an equine model that closely mimics human disease. Tendon injury was induced in the superficial digital flexor tendon (SDFT) of 17 horses. Tendon lesions were treated 1 week later with an intralesional injection of miR29a or placebo. miR29a treatment reduced collagen 3 transcript levels at week 2, with no significant changes in collagen 1. The relative lesion cross-sectional area was significantly lower in miR29a tendons compared to control tendons. Histology scores were significantly better for miR29a-treated tendons compared to control tendons. These data support the mechanism of microRNA-mediated modulation of early pathophysiologic events that facilitate tissue remodeling in the tendon after injury and provides a strong proof of principle that a locally delivered miR29a therapy improves early tendon healing.

Effect of micro‐RNA on tenocytes and tendon‐related gene expression: A systematic review

“…Increased miR-29b led to decreased expression of TFG-B1 and the gliding excursion repaired tendon was increased Watts et al 32 miR-29a Equine Digital flexor tendon miR-29a replacement therapy resulted in downregulation of collagen III expression as well as decreased tendon lesion size versus control MICRO-RNA IN TENDINOPATHY and Col3 expression upon targeting EGR-1, 20 which is similar to the actions of miRNA-29b in collagen fiber inhibition. Micro-RNA-140 also demonstrated multiple functions, with upregulation of TGF-B1 while mediating the reduction in mechanical loading.…”

“…Application of miRNA downregulated collagen III but not collagen I Watts et al 32 miR-29a Equine Digital flexor tendon miR-29a replacement therapy decreased collagen III expression 20 miR-217 Human Achilles tendon P16 inhibits tenogenic differentiation of TSPCs, mediated by miR-217 and its target EGR1 Chen et al 18 MiR-135a Rats Achilles tendon…”

“…They demonstrate that IL-33, acting through NF-kB, downregulates miR-29a, suggesting that addition of miR-29a after tendon injury may improve tendon healing and recovery.This hypothesis was tested in a randomized control trial in which equines received miR-29a replacement therapy following superficial digital flexor tendon injury. 32…”

“…Col3 expression as well as decreased lesion size and improved histology scores for animals receiving treatment, 32 suggesting that miR-29a improves early tendon healing and modulates early pathophysiologic events that facilitate tendon tissue remodeling after injury. Other prominent micro-RNA featured in this review include miRNA-217, which was shown to target EGR-1 20 and acted to increase tenogenic differentiation in young TSPCs.…”

MicroRNA Profiling Reveals Distinct Signatures in Degenerative Rotator Cuff Pathologies

“…By controlling interleukin 33 syntheses, miR‐29a positively regulated collagen 3 (Col‐3) expression in tenocytes and miR‐29a downregulation was correlated with the overexpression of Col‐3, resulting in an unbalanced ratio of collagen type 1 and 3, which is a hallmark of tendon degeneration. Further, in an equine therapeutic model Watts et al demonstrated a significant reduction of Col‐3 synthesis by overexpression of miR‐29a, illustrating the important role of miRNAs in fine‐tuning ECM composition in tendon tissue …”