Interleukin-1 (IL-1)-induced suppression of cytokine signaling (SOCS) 3 renders chondrocytes insensitive to insulin-like growth factor-1 (IGF-1), a novel mechanism that appears to contribute to cartilage damage in arthritis, according to research presented earlier this month at the 10th World Congress of the Osteoarthritis Research Society International (OARSI) in Boston, Massachusetts.

"We found many years ago that interleukin-1 induces suppression [of proteoglycan synthesis in otherwise healthy cartilage], but that the suppression can be counteracted by growth factors [notably IGF-1], which stimulate proteoglycan synthesis," says principal investigator Fons A.J. van de Loo, PhD, program leader of gene therapy research in the department of rheumatology research and advanced therapeutics at Radboud University Nijmegen Medical Centre in the Netherlands. However, that's not the case in arthritis, Dr. van de Loo says.

In the study, the Dutch investigators induced arthritis in murine patellar chondrocytes, then exposed the chondrocytes to IL-1. IL-1 all but blocked induction of proteoglycan synthesis by IGF-1.

"In healthy joints, there is a balance between anabolism and catabolism, but in disease, catabolic processes cause proteoglycan degradation. One wouldn't expect this to be a problem, however," Dr. van de Loo tells CIAOMed, "because chondrocytes can generate new proteoglycans."

Dr. Van de Loo was aware that members of the "cytokine signaling suppressor" family of proteins could suppress IGF and insulin signaling, and had also been implicated in liver-insulin resistance, diabetes, and obesity, so his suspicion that they might be involved in suppression of IGF in arthritic chondrocytes was justified. Just one day after arthritis was induced, Dr. van de Loo found that the SOCS protein was highly expressed in the murine patellar chondrocytes. "If you overexpress SOCS3, the cells become insensitive to IGF," he explains.

Linda Sandell, PhD, professor and director of research in the department of orthopaedic surgery, at Washington University School of Medicine in St. Louis, tells CIAOMed, "I'm interested [in this research] because this is a new mechanism for down-regulation of type II collagen, and because we have wondered why IGF-1, which stimulates collagen production in normal chondrocytes, does not stimulate it in osteoarthritic chondrocytes."

Summing up, Dr. van de Loo says, "IL-1 can directly induce IGF-1 nonresponse, and this nonresponse is mediated in chondrocytes by SOCS." Since SOCS can bind to IGF-1, this prevents recruitment of insulin receptor substrate (IRS)-1, he says.

Reference

1. Van der Loo FAJ, Smeets RL, Veenbergen S, et al. A novel role for SOSC3 in cartilage destruction via induction of chondrocyte desensitization toward IGF-1. Presented at: 10th World Congress of the Osteoarthritis Research Society International (OARSI); December 8–11, 2005; Boston, Mass. Abstract A42.