p16INK4a and its regulator miR-24 link senescence and chondrocyte terminal differentiation-associated matrix remodeling in osteoarthritis

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Abstract

Introduction

Recent evidence suggests that tissue accumulation of senescent p16 ^INK4a-positive cells during the life span would be deleterious for tissue functions and could be the consequence of inherent age-associated disorders. Osteoarthritis (OA) is characterized by the accumulation of chondrocytes expressing p16 ^INK4a and markers of the senescence-associated secretory phenotype (SASP), including the matrix remodeling metalloproteases MMP1/MMP13 and pro-inflammatory cytokines interleukin-8 (IL-8) and IL-6. Here, we evaluated the role of p16 ^INK4a in the OA-induced SASP and its regulation by microRNAs (miRs).

Methods

We used IL-1-beta-treated primary OA chondrocytes cultured in three-dimensional setting or mesenchymal stem cells differentiated into chondrocyte to follow p16 ^INK4a expression. By transient transfection experiments and the use of knockout mice, we validate p16 ^INK4a function in chondrocytes and its regulation by one miR identified by means of a genome-wide miR-array analysis.

Results

p16 ^INK4a is induced upon IL-1-beta treatment and also during in vitro chondrogenesis. In the mouse model, Ink4a locus favors in vivo the proportion of terminally differentiated chondrocytes. When overexpressed in chondrocytes, p16 ^INK4a is sufficient to induce the production of the two matrix remodeling enzymes, MMP1 and MMP13, thus linking senescence with OA pathogenesis and bone development. We identified miR-24 as a negative regulator of p16 ^INK4a. Accordingly, p16 ^INK4a expression increased while miR-24 level was repressed upon IL-1-beta addition, in OA cartilage and during in vitro terminal chondrogenesis.

Conclusions

We disclosed herein a new role of the senescence marker p16 ^INK4a and its regulation by miR-24 during OA and terminal chondrogenesis.

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Age-related changes in multiple components of the musculoskeletal system may contribute to the well established link between aging and osteoarthritis (OA). This review focused on potential mechanisms by which age-related changes in the articular cartilage could contribute to the development of OA. The peer-reviewed literature published prior to February 2009 in the PubMed database was searched using pre-defined search criteria. Articles, selected for their relevance to aging and articular chondrocytes or cartilage, were summarized. Articular chondrocytes exhibit an age-related decline in proliferative and synthetic capacity while maintaining the ability to produce pro-inflammatory mediators and matrix degrading enzymes. These findings are characteristic of the senescent secretory phenotype and are most likely a consequence of extrinsic stress-induced senescence driven by oxidative stress rather than intrinsic replicative senescence. Extracellular matrix changes with aging also contribute to the propensity to develop OA and include the accumulation of proteins modified by non-enzymatic glycation. The effects of aging on chondrocytes and their matrix result in a tissue that is less able to maintain homeostasis when stressed, resulting in breakdown and loss of the articular cartilage, a hallmark of OA. A better understanding of the basic mechanisms underlying senescence and how the process may be modified could provide novel ways to slow the development of OA.

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Author and article information

Contributors

Didier Philipot

David Guérit

Daniela Platano

Paul Chuchana

Eleonora Olivotto

Francisco Espinoza

Anne Dorandeu

Yves-Marie Pers

Jacques Piette

Rosa Maria Borzi

Christian Jorgensen

Danièle Noel

Jean-Marc Brondello

Journal

Journal ID (nlm-ta): Arthritis Res Ther

Journal ID (iso-abbrev): Arthritis Res. Ther

Title: Arthritis Research & Therapy

Publisher: BioMed Central

ISSN (Print): 1478-6354

ISSN (Electronic): 1478-6362

Publication date (Print): 2014

Publication date (Electronic): 27 February 2014

Volume: 16

Issue: 1

Page: R58

Affiliations

[1 ]INSERM U844, CHU St Eloi, Bat INM, 80 av A. Fliche, 34298 Montpellier, cedex 05, France

[2 ]Université de Montpellier-1, UFR de Medecine, F-34000, Montpellier, France

[3 ]Laboratorio di immunoreumatologia e rigenerazione tissutale, IOR, Istituto di ricerca Codivilla Putti, I-40136 Bologna, Italy

[4 ]Service de Medecine légale CHU La Peyronie, F34000 Montpellier, France

[5 ]Unité clinique, thérapeutiques des maladies des os et articulations, CHU Lapeyronie, F34000 Montpellier, France

[6 ]UMR5237, CNRS, CRBM, 1919 route de Mende, F34295 Montpellier, France

Article

Publisher ID: ar4494

DOI: 10.1186/ar4494

PMC ID: 4060445

PubMed ID: 24572376

SO-VID: b8f198e8-e290-4b00-b3c7-f89ca1e6cc57

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.