Study identifies molecular response of cartilage to injury

It’s an unfortunate fact backed by studies of former professional football and soccer players: injury to joint cartilage escalates the risk of developing of osteoarthritis (OA). However, why this occurs—the details of how joint cartilage cells respond to acute trauma and how this response leads to progressive cartilage degradation—remains open to investigation.

To shed further light on this issue of intense research interest, an international team of rheumatologists and biotechnologists conducted a microarray screening of adult human joint cartilage subjected to injury. Led by Dr. Francesco Dell’Accio, a Clinician Scientist Fellow of the Arthritis Research Campaign, the team reported in the May issue of Arthritis & Rheumatism (www.interscience.wiley.com/journal/arthritis) the full-genome characterization of the moleculer response of adult human articular cartilage to mechanical injury.

The gene expression profile of cartilage explants 24 hours after mechanical injury was compared to that of uninjured control explants using microarray technology. The explants were obtained either from uninvolved cartilage areas of knees affected by OA or from healthy cartilage from one individual who underwent a limb amputation following a road traffic accident. The expression of selected genes was then confirmed using real time PCR and immunohistochemistry.

In the injured samples, a total of 690 genes were significantly either up- or downregulated at least 2-fold compared with expression in the uninjured samples. Significant clusters included genes associated with cell signaling, wound healing, and skeletal development, as well as genes previously found to be differentially expressed in OA cartilage. Members of the WNT, TGFâ, and FGF family of signalling molecules were included in the regulated gene list. A targeted analysis of the Wnt signaling pathway in injured cartilage revealed up-regulation of the ligand Wnt-16, down-regulation of the secreted inhibitor FRZB, nuclear accumulation of â-catenin, and upregulation of several known WNT target genes supporting net activation of this signalling pathway. Wnt-16 and â-catenin were barely detectable in preserved cartilage from OA joints but dramatically up-regulated in areas of the same joint with moderate to severe OA damage.

This study indicates that several genes encoding signalling molecules are regulated following cartilage injury in adult individuals. Although it is tempting to speculate that some of these genes represent a reparative response, Dr Dell’Accio stresses that at the moment we do not know whether such phenomena are supporting repair (hence representing potential therapeutic tools) or even play a role in the progression of damage (hence potential therapeutic targets). Hence further investigation is needed “to optimally target the respective pathways to promote joint surface cartilage defect repair or to stop further joint surface breakdown, thereby preventing the development of posttraumatic OA.”

In a related editorial, Dr. Tonia L. Vincent and Dr. Jeremy Saklatva of Imperial College London raise the question of whether the response of cartilage to injury is relevant to osteoarthritis. As they argue, the findings of Dr. Dell’Accio and his colleagues suggest that Wnt activity may be important in OA, possibly driving bone changes in disease, such as osteophyte formation, but not necessarily directly injury-regulated. Yet, as they also note, studies devoted to unraveling the link between joint injury and OA risk are leading the way toward a better understanding of the tissue processes and the signaling pathways activated in disease. “Further investigation into the pathways revealed in this injury microarray is likely to be highly informative,” Dr. Vincent states.

Article: “Identification of the Molecular Response of Articular Cartilage to Injury, by Microarray Screening: Wnt-16 Expression and Signaling After Injury and in Osteoarthritis,” Francesco Dell’Accio, Cosimo De Bari, Noha M. Eltawil, Paul Vanhummelen, and Costantino Pitzalis, Arthritis & Rheumatism, May 2008; 58:5 pp. 1410-1421. Editorial: “Is the Response of Cartilage to Injury Relevant to Osteoarthritis,” Tonia L. Vincent and Jeremy Saklatvala, Arthritis & Rheumatism, May 2008; 58:5 pp. 1207-1210.

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