The US Census Bureau estimated that 35 million American will be 65 years or older by the Year 2000. Osteoarthritis [OA] and pseudogout are the most common afflictions of aging. Crystalline calcium pyrophosphate dihydrate [CPPD] and basic calcium phosphate [BCP] are the 2 most common forms of pathologic articular mineral. Each occurs frequently in OA joints, and each may be phlogistic, causing acute attacks of pseudogout (CPPD) and acute calcific periarthritis (BCP). The incidence of both calcium crystal arthritides significantly increases with age. The overall objective of this proposal is to determine the pathogenesis of the degenerative arthropathies associated with the deposition of CPPD and BCP crystals in articular tissues with the eventual goal of developing a rational means of preventing or reversing the consequences of such deposition. The paradigm of our work is that crystals can cause the degeneration of articular tissues. Crystals induce fibroblast-like synoviocytes to proliferate and produce metalloproteinases [MMP] and prostaglandins [PG], which eventually cause the degeneration of articular tissues. Phosphocitrate, a specific inhibitor of calcium crystals, reverses the degenerative effects of crystals. We are requesting funding to elucidate the mechanism of interaction of crystals and plasma membrane and the subsequent signal pathways leading the activation of various transcription factors and ultimately MMP synthesis and mitogenesis. The overall Hypothesis is that the interaction of crystals with specific components in plasma membrane resulted in MMP expression primarily through a Ras/ERK 1 and 2 Mitogen-activated Protein Kinase (MAPK)/Serum Response Factor (SRF)/c-fos /AP-1 dependent signaling pathway. New treatment strategies that might ameliorate the degenerative process may ensue from new information about how crystals form and how they exert their biologic effects. We shall test 5 inter-related sub-hypothesis: Hypothesis 1: Cell activation by crystals is due to the physical interaction of crystal surface with specific components of the cell membrane e.g. phospholipid. Hypothesis 2: SRF mediates BCP crystal- induced cell activation. Hypothesis 3: BCP crystals induce MMP-1 via a Ras-dependent p42/44 MAPK signal transduction pathway. Hypothesis 4: There are specific cis elements in the promoter of MMP-1 and -13 that regulates crystal-induced MAP synthesis. Hypothesis 5: There are specific cis elements in the promotor of Tissue Inhibitor of Metalloproteinase (TIMP)-2 that regulate crystal inhibition of TIMP- 2 expression.
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