IL-1 regulation of collagenase-3 (MMP-13) gene expression in chondrocytic cells

The matrix metalloproteinases (MMPs) are family of enzymes with a common domain structure that degrade extracellular matrix proteins; these enzymes are overexpressed in numerous diseases including cancer and arthritis. Collagenase-1, 2, 3 (MMP-1, 8, 13) and MT1-MMP are the only known enzymes capable of cleaving triple helical collagens Type-I, II, and III: thus, their presence is the rate limiting step for proteolytic cleavage of collagens. The collagens are the most abundant proteins in the body, providing structural and tensile strength to tissues. Proteolytic degradation of collagens in cartilage, tendon, and bone cause irreversible joint destruction in arthritis. In Osteoarthritis, slow cartilage degradation results from chondrocyte proteinase secretion and cleavage of type-II collagen. Collagenase-3 (MMP-13) can digest a wide range of matrix components, including type-II collagen in cartilage and its expression co-localizes with active osteoarthritic lesions, The expression of MMP-13 in cartilage is believed to result from autocrine IL-1 secretion by chondrocytes, the mechanism by which IL-1 induces MMP-13 gene expression was unknown. I set out to define the signaling pathways induced by IL-1 that regulate MMP-13 expression, and to discover the cis-acting DNA sequences in the MMP-13 promoter that regulate MMP-13 transcription. I determined that IL-1 induced a strong MMP-13 transcriptional response that required protein synthesis. I found that p38, c-Jun N-terminal kinase (JNK) mitogen activated protein kinases (MAPKs), and the transcription factor Nuclear factor kappa B (NF-kappaB) were required for IL-1 induction of MMP-13. Additionally, I demonstrated that cis-acting sequences in the first 405 base pairs of the MMP-13 promoter are sufficient and require chromosomal integration for IL-1 induction of MMP-13 transcription, implying that chromatin structure is important for regulation of this gene. Moreover, the transcription factor Runx-2 was required for tissue specific IL-1 induction of MMP-13; this factor appears to be an integration point with IL-1 induced MAPK signaling, In summary, IL-1 regulation of MMP-13 requires activation of MAPK pathways and NF-kappaB; these pathways converge at the MMP-13 promoter through the transcription factor Runx-2 to control MMP-13 transcription.