Basic Calcium Phosphate Crystals Induce Matrix Metalloproteinase-1 through the Ras/Mitogen-activated Protein Kinase/c-Fos/AP-1/Metalloproteinase 1 Pathway

Abstract

Synovial fluid basic calcium phosphate (BCP) crystals are common in osteoarthritis and are associated with severe degenerative arthropathy. Besides stimulating synovial fibroblast-like cells to proliferate, BCP crystals are a potent inducer of human matrix metalloproteinases (hMMPs), which can speed up the articular joint tissue degeneration of osteoarthritis patients. Here, we report that transfections with hMMP1 luciferase reporter plasmids in fibroblast-like synoviocytes revealed that the induction of hMMP1 promoter by BCP crystals was mainly mediated through the ؊72AP-1 element. Elimination of the ؊72AP-1 element either by mutation or deletion abolished the induction of hMMP1 promoter activity by BCP crystals almost completely. Interestingly, a mutation at the ؊88PEA-3 site also abolished the induction of hMMP1 promoter. Further mutation at the ؊181AP-1 site resumed the induction, indicating that the ؊181AP-1 element had an effect opposite to the ؊72AP-1 element. The effect of ؊181AP-1 could be inactivated either by a mutation at this ؊181AP-1 site or by the ؊88PEA-3 element. In addition, dominant negative Ras, Raf, and MEK1/2 could block the induction of hMMP1, and a MEK1/2-specific inhibitor (UO126) could block the induction of hMMP1 and c-Fos by BCP crystals. Taken together, these data indicate that multiple elements, including at least AP-1 and PEA-3, are involved in the induction of hMMP1 gene expression by BCP crystals and that the induction follows the Ras/ MAPK/c-Fos/AP-1/MMP1 signaling pathway.

Induction of matrix metalloproteinase 1 gene expression is regulated by inflammation‐responsive transcription factor SAF‐1 in osteoarthritis

“…In addition, a polyoma virus enhancer 3 (PEA-3) binding site at the proximal promoter region is also involved in the induction of human MMP1 (16). Interestingly, AP-1 has been shown to interact with PEA-3 (17) and SMAD proteins (17,18), and such an interaction potentiates the activity of AP-1.…”

Adaptor Proteins and Ras Synergistically Regulate IL-1-Induced ADAMTS-4 Expression in Human Chondrocytes

“…Such inhibitors also reduce severity of collagen-induced arthritis (an animal model of RA) by suppressing Ras and IKK-mediated activation of NF-B (53). Previously observed suppression of bone destruction by dominant negative Ras may be partly due to inhibition of proteases such as ADAMTS-4 and MMPs (54,55).…”

Suppression of Oxidized LDL-Induced PDGF Receptor .BETA. Activation by Ginkgo Biloba Extract Reduces MMP-1 Production in Coronary Smooth Muscle Cells

“…The current study showed that Ginkgolon-24, an extract of Ginkgo Biloba L., suppressed the production of MMP-1 induced by oxLDL and 4-HNE in hCSMCs, suggesting that this inhibitory activity is also involved in the therapeutic effects of the extract on cardiovascular disorders 28) and intimal hyperplasia in ballooninjured abdominal aorta in an animal model 29) . With regard to the mechanisms responsible for the production of MMP-1, the induction of MMP-1 gene expression was mediated by ERK1/2 in canine fibroblast-like synoviocytes 34) . The activation of ERK1/2 was mediated by the activation of receptors for growth factors such as PDGFR-in SMCs 36,37) .…”

“…Stimulation of hCSMCs with oxLDL (50 g/mL) for 24h induced an increase in MMP-1 protein in the culture medium, as estimated by immunoblotting, as shown in The induction of MMP-1 gene expression is suggested to be mediated by ERK1/2 in canine fibroblastlike synoviocytes stimulated with basic calcium phosphate crystals 34) . We also reported that oxLDL and 4-HNE induces the activation of ERK1/2, inhibition of which by PD98059, an inhibitor of mitogen-activated protein kinase/ERK kinase, resulted in the suppression of MMP-1 production in hCSMCs 15) , suggesting the involvement of ERK1/2 in the production of MMP-1.…”