Transcriptomics of Wild‐Type Mice and Mice Lacking ADAMTS‐5 Activity Identifies Genes Involved in Osteoarthritis Initiation and Cartilage Destruction. Issue 6 (30th May 2013)

• Record Type: Journal Article
• Authors: Bateman, John F.; Rowley, Lynn; Belluoccio, Daniele; Chan, Ben; Bell, Katrina; Fosang, Amanda J.; Little, Christopher B.
• Is Part Of: Arthritis and rheumatism. Volume 65:Issue 6(2013:Jun.)
• Page Start: 1547
• Page End: 1560
• Publication Date: 2013-05-30
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; Arthritis -- Periodicals; Rheumatic Diseases -- Periodicals; Rhumatisme -- Périodiques; Arthrite -- Périodiques; 616.72
• DOI: 10.1002/art.37900
• Languages: English
• ISSNs: 0004-3591

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="art37900-sec-0001" sec-type="section"> <title>Objective</title> <p>To identify changes in gene expression in mice with osteoarthritis (OA) in order to explore the mechanisms of the disease.</p> </sec> <sec id="art37900-sec-0002" sec-type="section"> <title>Methods</title> <p>Gene expression profiling was performed in cartilage from mice with surgically induced OA. We used wild‐type (WT) mice and <italic>Adamts5</italic>Δcat mice, in which ADAMTS‐5 activity is lacking and aggrecan loss and cartilage erosion are inhibited, to distinguish gene expression changes that are independent of ADAMTS‐5 activity and cartilage breakdown. Mechanical instability was introduced into the knee joints of 10‐week‐old male mice via surgical destabilization of the medial meniscus (DMM). Cartilage from the developing lesion in the destabilized medial meniscus and corresponding regions in sham‐operated joints was harvested by microdissection at 1, 2, and 6 weeks postsurgery, and RNA was extracted, amplified, and hybridized to whole‐genome microarrays.</p> </sec> <sec id="art37900-sec-0003" sec-type="section"> <title>Results</title> <p>Several previously identified OA‐related genes, including <italic>Ptgs2, Crlf1, </italic> and <italic>Inhba</italic>, and novel genes, such as <italic>Phdla2</italic> and <italic>Il11, </italic> were up‐regulated in both WT mice and <italic>Adamts5</italic>Δcat mice, indicating that they are independent of ADAMTS‐5 activity. The altered expression of other genes, including <italic>Col10a1</italic>, the sentinel marker of cartilage hypertrophy, and Wnt/β‐catenin pathway genes, required ADAMTS‐5 activity. Cell death pathway genes were dysregulated, and Tp53, Foxo4, and Xbp1 endoplasmic reticulum–stress transcriptional networks were activated. Analysis of degradome genes identified up‐regulation of many proteases, including <italic>Mmp3</italic>, <italic>Capn2, </italic> and the novel cartilage proteases <italic>Prss46</italic> and <italic>Klk8</italic>. Comparison with other studies identified 16 genes also dysregulated in rat and human OA as priorities for study.</p> </sec> <sec id="art37900-sec-0004" sec-type="section"> <title>Conclusion</title> <p>We have identified, for the first time, several genes that have an ADAMTS‐5–independent role in OA, identifying them as possible OA initiation candidates. This work provides new insights into the sequence of gene dysregulation and the molecular basis of cartilage destruction in OA.</p> </sec> </abstract>