Cytokine Receptor-Like Factor 1 is Highly Expressed in Damaged Human Knee Osteoarthritic Cartilage and Involved in Osteoarthritis Downstream of TGF-β

Abstract

Osteoarthritis (OA) is the most prevalent joint disease and is characterized by pain and functional loss of the joint. However, the pathogenic mechanism of OA remains unclear, and no drug therapy for preventing its progress has been established. To identify genes related to the progress of OA, the gene expression profiles of paired intact and damaged cartilage obtained from OA patients undergoing joint substitution were compared using oligo microarrays. Using functional categorization combined with gene ontology and a statistical analysis, five genes were found to be highly expressed in damaged cartilage (HBEGF, ASUS, CRLF1, LOX, CDA), whereas three genes were highly expressed in intact tissues (CHST2, PTPRD, CPAN6). Among these genes, the upregulated expression of CRLF1 was reconfirmed using real-time PCR, and the in vivo expression of CRLF1 was detected in clusters of chondrocytes and fibrocartilage-like cells in damaged OA cartilages using in situ hybridization. In vitro, the transcriptional level of CRLF1 was positively regulated by TGF-beta1 in the mouse chondrogenic cell line ATDC5. Additionally, the CRLF1/CLC complex promoted the proliferation of ATDC5 cells and suppressed the expression level of aggrecan and type II collagen. Our data suggest that the CRLF1/CLC complex disrupts cartilage homeostasis and promotes the progress of OA by enhancing the proliferation of chondrocytes and suppressing the production of cartilage matrix. A component of the complex, CRLF1, may be useful as a biomarker of OA; and the corresponding receptor is a potential new drug target for OA.

Pain Perception in Knees With Circumscribed Cartilage Lesions Is Associated With Intra-articular IGF-1 Expression

“…There are only a few studies that address the issue of synovial or serum expression of cartilage-specific markers in patients with early-stage knee OA and limited synovitis in association with outcome and pain perception. In addition to our data about IGF-I, it has been shown that chondroitin 6-sulfate (C6S), chondroitin 4-sulfate (C4S), keratan sulfate (KS), and tenascin-C (TN-C), 19 cytokine receptor-like factor 1 (downstream of TGF-b), 47 or increased serum COMP (cartilage oligomeric matrix protein) levels 12 play a role as indicators or mediators in this stage of disease development. Because of its observational character, the study does not allow drawing any conclusions of how IGF-I is acting in detail, and it also remains unclear what molecular mechanisms are behind the observed association between synovial IGF-I levels and pain perception.…”

Genes Involved in the Osteoarthritis Process Identified through Genome Wide Expression Analysis in Articular Cartilage; the RAAK Study

“…Cartilage was classified macroscopically and collected separately from OA affected and preserved regions around the weight-bearing area of the joint (Figure S1). Classification was done based on predefined features of OA related damage as described previously [9], [10]: color/whiteness of the cartilage, surface integrity as determined by visible fibrillation/crack formation, and depth and hardness of the cartilage upon sampling with a scalpel. Care was taken to avoid contamination with bone or synovium.…”

Cardiotrophin-like cytokine factor 1 (CLCF1) and neuropoietin (NP) signalling and their roles in development, adulthood, cancer and degenerative disorders

“…In the degenerative joint condition of osteoarthritis, CRLF1 has been identified as a potential mediator of chondrocyte damage by 2 independent microarray studies of patient samples [55,56]. Expression in dysmorphic chondrocyte clusters [55] suggests a role that promotes cartilage degeneration in this common condition.…”

“…Expression in dysmorphic chondrocyte clusters [55] suggests a role that promotes cartilage degeneration in this common condition. CRLF1 levels in the chondrocyte cell line ATDC5 were promoted by transforming growth factor (TGF) b, and addition of CLCF1/CRLF1 to these CNTFR-expressing cells suppressed their expression of aggrecan and type II collagen (components of the healthy cartilage matrix) [55]. Crlf1 mRNA was rapidly upregulated in a mouse surgical model of osteoarthritis and did not depend on aggrecan degradation by ADAMTS5 [57].…”