MicroRNA29a regulates IL-33-mediated tissue remodelling in tendon disease

Abstract

MicroRNA (miRNA) has the potential for cross-regulation and functional integration of discrete biological processes during complex physiological events. Utilizing the common human condition tendinopathy as a model system to explore the cross-regulation of immediate inflammation and matrix synthesis by miRNA we observed that elevated IL-33 expression is a characteristic of early tendinopathy. Using in vitro tenocyte cultures and in vivo models of tendon damage, we demonstrate that such IL-33 expression plays a pivotal role in the transition from type 1 to type 3 collagen (Col3) synthesis and thus early tendon remodelling. Both IL-33 effector function, via its decoy receptor sST2, and Col3 synthesis are regulated by miRNA29a. Downregulation of miRNA29a in human tenocytes is sufficient to induce an increase in Col3 expression. These data provide a molecular mechanism of miRNA-mediated integration of the early pathophysiologic events that facilitate tissue remodelling in human tendon after injury.

Wounds that heal and wounds that don’t − The role of the IL-33/ST2 pathway in tissue repair and tumorigenesis

“…Moreover, miR-29a overexpression significantly decreased IL-33-induced collagen 3 mRNA and protein synthesis. In addition, miR-29a inhibition resulted in a significant increase in COL 3A1 expression, indicating that miR-29a is not only actively regulating these transcripts in human tenocytes but its loss can be an important factor in the increase of type 3 collagen production observed in tendinopathy [61]. In contrast, COL 1A1 and A2 transcript levels were relatively unchanged.…”

“…All members of the miR-29 family were expressed in human tendon biopsies and explanted tenocytes with miR-29a showing the most altered expression in early tendinopathy biopsies. In tenocyte culture, IL-33 significantly reduced the expression of miR-29a, in an NF-κB, dependent manner [61]. miR-29a manipulation selectively regulated collagen 3 but not collagen 1 mRNA and protein expression in primary tenocytes.…”

Tendon injury and repair – A perspective on the basic mechanisms of tendon disease and future clinical therapy

“…Collagen III synthesis is understood to be involved in early stages of wound repair, following on fibronectin matrix templating by tendon fibroblasts [61]. Increased presence of collagen III is considered to be a hallmark of degeneration, with adverse effects reflected in tissue disorder and reduced mechanical properties [62]. In lesser quantities, collagen V is another fibrillar protein present in tendon that plays a key role in ordering and stabilizing type-I collagen structures during collagen I self-assembly [63].…”

Tendon healing induced by chemically modified mRNAs

“…Besides degenerative processes, failed healing response and inflammation have also been proposed as causative agents for tendinopathies (Del Buono et al, 2011;Maffulli et al, 2010). Millar et al (2015) demonstrated that, in human and experimentally injured tendons, elevated IL-33 expression is a characteristic of early tendinopathy and identified miRNA29a as key regulator of IL-33 function and excessive collagen type III synthesis. Their data provide a molecular mechanism of microRNA-mediated integration of the early pathophysiologic events that facilitate tissue remodelling in human tendon after injury.…”