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

Millar NL, Gilchrist DS, Akbar M, Reilly JH, Kerr SC, Campbell AL, Murrell GA, Liew FY, Kurowska-Stolarska M, McInnes IB - Nat Commun (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences University of Glasgow, Glasgow G12 8QQ, UK.

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.

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IL-33/anti-IL-33 effects on collagen production and tendon strength in vivo.(a) Col1 mRNA, (b) Collagen 1 protein, (c) Col3 mRNA and (d) Collagen 3 protein in WT and St2−/− mice on day 1 post injury. mRNA graphs show relative expression to 18s housekeeping gene. Data are mean±s.d. of duplicate samples, representative of four mice per condition (n=16). *P<0.05,**P<0.01, injured versus uninjured mice.+P<0.05 WT versus ST2−/− mice. (ANOVA). (e) Percentage change in tendon strength in WT and St2−/− mice on day 1 post injury with or without rhIL-33 treatment. Data are mean±s.d., representative of four mice per group (n=16). **P<0.01, injured versus injured+IL-33 mice (Mann–Whitney U-test). (f) Col1 mRNA, (g) Collagen 1 protein, (h) Col3 mRNA, (i) Collagen 3 protein levels and (j) percentage change in tendon strength post tendon injury in WT mice with or without anti-IL-33 treatment. Data for mRNA show relative expression to 18s housekeeping gene. Data are mean±s.d., representative of four mice per condition (n=16). *P<0.05, **P<0.01, injured versus uninjured mice (Mann–Whitney U-test).
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f3: IL-33/anti-IL-33 effects on collagen production and tendon strength in vivo.(a) Col1 mRNA, (b) Collagen 1 protein, (c) Col3 mRNA and (d) Collagen 3 protein in WT and St2−/− mice on day 1 post injury. mRNA graphs show relative expression to 18s housekeeping gene. Data are mean±s.d. of duplicate samples, representative of four mice per condition (n=16). *P<0.05,**P<0.01, injured versus uninjured mice.+P<0.05 WT versus ST2−/− mice. (ANOVA). (e) Percentage change in tendon strength in WT and St2−/− mice on day 1 post injury with or without rhIL-33 treatment. Data are mean±s.d., representative of four mice per group (n=16). **P<0.01, injured versus injured+IL-33 mice (Mann–Whitney U-test). (f) Col1 mRNA, (g) Collagen 1 protein, (h) Col3 mRNA, (i) Collagen 3 protein levels and (j) percentage change in tendon strength post tendon injury in WT mice with or without anti-IL-33 treatment. Data for mRNA show relative expression to 18s housekeeping gene. Data are mean±s.d., representative of four mice per condition (n=16). *P<0.05, **P<0.01, injured versus uninjured mice (Mann–Whitney U-test).

Mentions: To confirm that IL-33 regulates collagen synthesis during tendon injury, we sought to directly modify IL-33 effector function in vivo. Administration of rhIL-33 did not affect collagen 1 synthesis (Fig. 3a,b), but significantly increased collagen 3 synthesis particularly in injured tendons (Fig. 3c,d and Supplementary Fig. 4a,b). Moreover, rhIL33 administration significantly reduced ultimate tendon strength at all time points post injection in WT mice (Fig. 3e and Supplementary Fig. 4c,d) suggesting that such changes were of functional impact. IL-33 administration did not affect collagen matrix synthesis or ultimate tendon strength of the healing tendon in St2−/− mice confirming that IL-33 acted via an ST2-dependent pathway (Supplementary Fig. 4).


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

Millar NL, Gilchrist DS, Akbar M, Reilly JH, Kerr SC, Campbell AL, Murrell GA, Liew FY, Kurowska-Stolarska M, McInnes IB - Nat Commun (2015)

IL-33/anti-IL-33 effects on collagen production and tendon strength in vivo.(a) Col1 mRNA, (b) Collagen 1 protein, (c) Col3 mRNA and (d) Collagen 3 protein in WT and St2−/− mice on day 1 post injury. mRNA graphs show relative expression to 18s housekeeping gene. Data are mean±s.d. of duplicate samples, representative of four mice per condition (n=16). *P<0.05,**P<0.01, injured versus uninjured mice.+P<0.05 WT versus ST2−/− mice. (ANOVA). (e) Percentage change in tendon strength in WT and St2−/− mice on day 1 post injury with or without rhIL-33 treatment. Data are mean±s.d., representative of four mice per group (n=16). **P<0.01, injured versus injured+IL-33 mice (Mann–Whitney U-test). (f) Col1 mRNA, (g) Collagen 1 protein, (h) Col3 mRNA, (i) Collagen 3 protein levels and (j) percentage change in tendon strength post tendon injury in WT mice with or without anti-IL-33 treatment. Data for mRNA show relative expression to 18s housekeeping gene. Data are mean±s.d., representative of four mice per condition (n=16). *P<0.05, **P<0.01, injured versus uninjured mice (Mann–Whitney U-test).
© Copyright Policy - open-access
Related In: Results  -  Collection

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f3: IL-33/anti-IL-33 effects on collagen production and tendon strength in vivo.(a) Col1 mRNA, (b) Collagen 1 protein, (c) Col3 mRNA and (d) Collagen 3 protein in WT and St2−/− mice on day 1 post injury. mRNA graphs show relative expression to 18s housekeeping gene. Data are mean±s.d. of duplicate samples, representative of four mice per condition (n=16). *P<0.05,**P<0.01, injured versus uninjured mice.+P<0.05 WT versus ST2−/− mice. (ANOVA). (e) Percentage change in tendon strength in WT and St2−/− mice on day 1 post injury with or without rhIL-33 treatment. Data are mean±s.d., representative of four mice per group (n=16). **P<0.01, injured versus injured+IL-33 mice (Mann–Whitney U-test). (f) Col1 mRNA, (g) Collagen 1 protein, (h) Col3 mRNA, (i) Collagen 3 protein levels and (j) percentage change in tendon strength post tendon injury in WT mice with or without anti-IL-33 treatment. Data for mRNA show relative expression to 18s housekeeping gene. Data are mean±s.d., representative of four mice per condition (n=16). *P<0.05, **P<0.01, injured versus uninjured mice (Mann–Whitney U-test).
Mentions: To confirm that IL-33 regulates collagen synthesis during tendon injury, we sought to directly modify IL-33 effector function in vivo. Administration of rhIL-33 did not affect collagen 1 synthesis (Fig. 3a,b), but significantly increased collagen 3 synthesis particularly in injured tendons (Fig. 3c,d and Supplementary Fig. 4a,b). Moreover, rhIL33 administration significantly reduced ultimate tendon strength at all time points post injection in WT mice (Fig. 3e and Supplementary Fig. 4c,d) suggesting that such changes were of functional impact. IL-33 administration did not affect collagen matrix synthesis or ultimate tendon strength of the healing tendon in St2−/− mice confirming that IL-33 acted via an ST2-dependent pathway (Supplementary Fig. 4).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences University of Glasgow, Glasgow G12 8QQ, UK.

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.

Show MeSH
Related in: MedlinePlus