MicroRNA Replacement: A New Era of Molecular Therapy for Tendon Disorders?
Authors: Stephanie G. Dakin
Journal: Molecular Therapy (2017)

Musculoskeletal soft tissue disorders affecting tendon and entheseal tissues are a significant global disease burden, cause chronic disability, and are exacerbated with aging.1Global Burden of Disease Study 2013 CollaboratorsGlobal, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.Lancet. 2015; 386: 743-800Google Scholar Tendinopathy is also a significant cause of morbidity and mortality in athletic and aged horses; hence, the horse is an excellent model for human tendon disease. Horses also show high prevalence of recurrent disease, analogous to the equivalent human condition. In this issue of Molecular Therapy, Watts et al.2Watts A.E. Millar N.L. Platt J. Kitson S.M. Akbar M. Rech R. Griffin J. Pool R. Hughes T. McInnes I.B. Gilchrist D.S. MicroRNA29a treatment improves early tendon injury.Mol Ther. 2017; 25 (this issue): 2415-2426Google Scholar report microRNA29a as a potential therapeutic target to improve tendon healing in an experimentally induced equine model of tendon disease (tendinopathy). They show that local delivery of microRNA29a (miR29a) improved early tendon healing, modulated gene expression of collagen 3, and improved tendon histological scores compared to a placebo control. Given that many small animal models of induced tendinopathy heal spontaneously and do not recapitulate the effects of aging and exercise overuse associated with naturally occurring disease, the equine study by Watts et al.2Watts A.E. Millar N.L. Platt J. Kitson S.M. Akbar M. Rech R. Griffin J. Pool R. Hughes T. McInnes I.B. Gilchrist D.S. MicroRNA29a treatment improves early tendon injury.Mol Ther. 2017; 25 (this issue): 2415-2426Google Scholar has translational potential to inform therapeutic strategies to treat human tendon disease. The study highlights the potential of microRNA replacement in a new era of molecular therapies for disorders affecting musculoskeletal soft tissues. The etiology of tendon disorders is multifactorial, encompassing the effects of repetitive exercise, aging, inflammation, and genetic factors.3Almekinders L.C. Temple J.D. Etiology, diagnosis, and treatment of tendonitis: an analysis of the literature.Med. Sci. Sports Exerc. 1998; 30: 1183-1190Google Scholar, 4Dudhia J. Scott C.M. Draper E.R. Heinegård D. Pitsillides A.A. Smith R.K. Aging enhances a mechanically-induced reduction in tendon strength by an active process involving matrix metalloproteinase activity.Aging Cell. 2007; 6: 547-556Google Scholar, 5Gwilym S.E. Watkins B. Cooper C.D. Harvie P. Auplish S. Pollard T.C. Rees J.L. Carr A.J. Genetic influences in the progression of tears of the rotator cuff.J. Bone Joint Surg. Br. 2009; 91: 915-917Google Scholar, 6Dakin S.G. Martinez F.O. Yapp C. Wells G. Oppermann U. Dean B.J. Smith R.D. Wheway K. Watkins B. Roche L. Carr A.J. Inflammation activation and resolution in human tendon disease.Sci. Transl. Med. 2015; 7: 311ra173Google Scholar Injured tendons heal by fibrotic repair rather than replacement with “neo-tendon”, resulting in alteration of the tendon extracellular matrix composition and inferior tissue mechanical properties. Tendon and entheseal tissues possess a low rate of turnover;7Heinemeier K.M. Schjerling P. Heinemeier J. Magnusson S.P. Kjaer M. Lack of tissue renewal in human adult Achilles tendon is revealed by nuclear bomb (14)C.FASEB J. 2013; 27: 2074-2079Google Scholar consequently, damage accumulated is long lasting and increases susceptibility to recurrent disease. Current treatment regimens for tendon disorders require prolonged convalescence and include controlled physical therapy, non-steroidal anti-inflammatory drugs (NSAIDs), local injections of glucocorticoids, or biological therapies, including platelet-rich plasma. Surgical management may be advocated where tendons tear or rupture, necessitating tissue debridement and augmented repair. However, the lack of multicenter placebo controlled clinical trials coupled with incomplete understanding of the pathobiology present considerable hurdles in the effective treatment of tendon and entheseal disease. In an era of advanced molecular therapies, novel approaches are being considered to treat orthopaedic disease. MicroRNAs suppress gene expression by inhibiting translation or inducing RNA degradation. Their diagnostic, prognostic, and therapeutic utility has been advocated for multiple inflammatory and fibrotic diseases, using models of carcinoma, hepatitis, and a variety of cancers.8Bertoli G. Cava C. Castiglioni I. MicroRNAs: New Biomarkers for Diagnosis, Prognosis, Therapy Prediction and Therapeutic Tools for Breast Cancer.Theranostics. 2015; 5: 1122-1143Google Scholar, 9Ishida M. Selaru F.M. miRNA-Based Therapeutic Strategies.Curr. Anesthesiol. Rep. 2013; 1: 63-70Google Scholar However, the potential of miRNA replacement therapy to modulate diseases of orthopedic soft tissues, such as tendons, has not been previously determined. Watts et al.2Watts A.E. Millar N.L. Platt J. Kitson S.M. Akbar M. Rech R. Griffin J. Pool R. Hughes T. McInnes I.B. Gilchrist D.S. MicroRNA29a treatment improves early tendon injury.Mol Ther. 2017; 25 (this issue): 2415-2426Google Scholar propose miR29a replacement therapy as a potential therapeutic tool to target dysregulated tendon repair during healing. The group previously identified microRNA29a as a post-transcriptional regulator of collagen by using in vitro human tenocyte cultures and murine models of tendon damage.10Millar N.L. Gilchrist D.S. Akbar M. Reilly J.H. Kerr S.C. Campbell A.L. Murrell G.A. Liew F.Y. Kurowska-Stolarska M. McInnes I.B. MicroRNA29a regulates IL-33-mediated tissue remodelling in tendon disease.Nat. Commun. 2015; 6: 6774Google Scholar In the new study, the authors chemically induced tendon injury in 17 horses and designed a randomized blinded trial to investigate the potential of miR29a replacement therapy to improve early tendon healing. Compared to a placebo control, the authors found that miR29a treatment reduced expression of collagen type III transcript levels and improved tendon histological scores at 2 and 16 weeks after treatment, respectively. These findings add to the current body of evidence that miR29a is implicated in tissue remodeling, a mechanism that is highly conserved between murine, equine, and human species. Given that tendon repair and remodeling occur over a period of months to years, further studies are required to determine the longer term effects of miR29a replacement therapy on tendon healing and whether this treatment has potential to reduce the likelihood of recurrent disease. In soft tissues with low rates of turnover and limited capacity to “regenerate”, early therapeutic intervention is pivotal to optimize the quality of the repaired tissue. Tendons have a highly organized microstructure, which contributes to their innate mechanical strength and elasticity. Collagen type I is the most abundant protein in tendons and is arranged hierarchically into increasingly larger subunits. With injury, this highly organized tissue architecture is disrupted, resulting in markedly increased cellularity, vascularization, and altered composition of the tendon matrix. Collagen type III is abundant during the early phase of tendon repair and constitutes a more disordered arrangement to the repairing tissue architecture.11Riley G. The pathogenesis of tendinopathy. A molecular perspective.Rheumatology (Oxford). 2004; 43: 131-142Google Scholar During the later remodeling phase of tendon repair, the microstructural organization improves and the proportion of collagen type I increases. However, the tissue architecture, matrix composition, and mechanical properties of healed tendon remain inferior to healthy tendon. Therapies that possess the capacity to modulate the structural and compositional components of soft tissues during repair represent an opportunity to potentially “fine tune” fibrosis. Advantages of this approach include an improved quality of the tissue repair and reduced likelihood of recurrent disease if the repaired tissue is no longer acting as “the weak link in the chain”. Given that fibrosis is irreversible, timely therapeutic intervention is preferable, although the optimal dosing regimens of agents that have the potential to modulate tissue repair are not known. To further investigate the efficacy of miRNA29a replacement therapy, future studies will need to determine if this treatment moderates the collagenous components of healing tendon at the protein level and determine the longer term effects of this treatment on tendon structure, composition, and tissue mechanical properties. A further important requirement is to ascertain if miRNA replacement therapy is associated with any off-target effects. The study by Watts et al.2Watts A.E. Millar N.L. Platt J. Kitson S.M. Akbar M. Rech R. Griffin J. Pool R. Hughes T. McInnes I.B. Gilchrist D.S. MicroRNA29a treatment improves early tendon injury.Mol Ther. 2017; 25 (this issue): 2415-2426Google Scholar utilized a collagenase induced model of equine tendon injury; however, the potential for miRNA replacement therapy to improve tendon healing is yet to be determined in naturally occurring tendon disease in horse and human. Going forward, we should embrace the new era of molecular therapies to treat musculoskeletal diseases. We must, however, be mindful that novel therapeutic strategies such as microRNA replacement therapy should address the underlying pathobiology, are safe, effective, and not associated with off-target effects. Optimum therapeutic dosage, regimens, and timing of these treatments remain to be determined such that these therapies can be delivered to the right patients during an appropriate therapeutic window. Harnessing the potential to “fine tune” fibrosis has broad therapeutic utility and may inform regimens to treat inflammatory and fibrotic disorders of connective tissues affecting orthopedic soft tissues and beyond. MicroRNA29a Treatment Improves Early Tendon InjuryWatts et al.Molecular TherapyJuly 28, 2017In BriefOveruse tendon injuries, namely, tendinopathies, are a complex multi-faceted tendon pathology and pose a significant clinical problem, particularly in musculoskeletal and sports-related medicine. In this issue of Molecular Therapy, Watts et al. (2017) establish a microRNA replacement therapy as a therapeutic option for early tendon injury. Full-Text PDF Open Archive