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Rheumatology

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Matthew P. Vincenti, PhD

Research Associate Professor

The Matrix Metalloproteinases (MMP) are a family of zinc and calcium-dependent endopeptidases that control the deposition of a wide range of matrix proteins during normal development and wound healing. MMP expression is elevated in diseases such rheumatoid arthritis, osteoarthritis and osteoporosis, leading to significant and permanent connective tissue destruction. MMP-1, MMP-13 and MMP-9 are secreted by synovial fibroblasts, chondrocytes, and osteoclasts, respectively. The inflammatory cytokines IL-1 and TNF promote expression of these enzymes by these cells, and this is thought to contribute directly to pathologic degradation of cartilage and bone.

Research in Dr. Vincenti’s laboratory examines IL-1-dependent stimulation of MMP-1 in synovial fibroblasts and chondrocytes. These studies have established that IL-1 activation of the nuclear factor-kappa B (NF-κB) and the extracellular signal regulated kinase (ERK) pathways are critical processes for transcriptional activation of MMP-1 in these cells. Ongoing research is defining specific components of these pathways that are involved. Specifically, they have found that RelA and Bcl-3 are two NF-κB family members that are absolutely required for gene activation. Furthermore, IL-1 activation of the ERK pathway leads to phosphorylation of the transcription factor C/EBPβ, which directly binds to the MMP-1 promoter and facilitates transcription.

A second project in the laboratory investigates a group of plant-derived compounds known as triterpenoids. These compounds inhibit inflammation and reduce inflammation-induced MMP gene expression. TP-222, which is a triterpenoid that is highly bioavailable through oral administration to mice, effectively inhibits MMP-13 gene expression by chondrocytes and MMP-9 expression by osteoclasts. They are particularly interested in the molecular mechanisms through which TP-222 reduces MMP mRNA levels in these cells. It is hoped that this work will lead to the development of novel drugs that block cartilage destruction in arthritis and bone erosion in arthritis and osteoporosis.