Calcium Pyrophosphate Deposition Disease Development and Biochemical Pathways for Molecular Modulation. - Introduction: Calcium pyrophosphate deposition disease (CPPD), or “pseudogout,” is an idiopathic metabolic arthropathy characterized by calcium pyrophosphate dihydrate (CPP) crystal deposition in and around joints, particularly in articular cartilage and fibrocartilage. CPPD afflicts 1.3-in-1000 adults overall, with incidence increasing dramatically with age, at over 21% of people by 60, and 50% of people over 80 years old presenting with this painful, disfiguring, and debilitating disease. While under 5% of CPPD cases are associated with the ANKH genetic locus, the mechanisms of the disease origin in most cases remains idiopathic. CPPD affects 30 million people worldwide, yet is highly understudied, with a dearth of research reports on disease models, systems biology approaches, and potential therapeutic interventions for this age-related disease. Significance: This research will test a high-risk, high-reward approach to understanding the dynamics of CPPD crystal arthropathy development in aging, addressing a major public health problem with rationally designed animal models. This research endeavors to elucidate quantifiable, dose-related molecular mechanisms of CPPD development to systemically improve heath for this understudied yet common joint arthropathy. Innovation: Few models of CPPD have been reported in the literature, with no model yet established to study CPPD disease origin, progression, or remedy. One possible CPPD disease model mechanism is elevated lactic acid levels, which has been widely associated with CPPD in the literature, although not yet directly and mechanistically tested as a possible disease-promoting substance. By controllably inducing CPPD in vivo, advanced metabolomic, phenomics and molecular studies can be performed to understand better the disease's progression and present molecular pathways for treatment and diagnostics, which are currently lacking. This proposal will explore mechanistic models of CPPD to drive future medicinal advances. Hypothesis: Calcium pyrophosphate dihydrate crystals form in vivo via elevated lactic acid and arthritic joint bone erosion-related mechanisms. Aim 1: To determine the in vivo CPP crystal prevalence, metabolomics, and phenomics of rabbits with degenerated knees administered lactic acid locally in the knee synovial capsule. Aim 2: To assess the in vivo CPP crystal prevalence, metabolomics, and phenomics of rabbits with degenerated knees and elevated systemic metabolic acidosis. Aim 3: To investigate the role of lactate dehydrogenase (LDH) in CPPD pathogenesis in degenerated rabbit knees. Expected Outcomes CPP crystals will be induced in vivo via a lactic acid and eroded-bone-related mechanisms. This research will putatively present a causal disease formation mechanism for CPPD, presenting the potential for future novel therapeutic interventions, diagnostics, and underlying disease mechanisms.
