Novel preclinical targets and therapies for treatment of osteoarthritis

Date
2014
Authors
Srinivasan, Padma Pradeepa
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University of Delaware
Abstract
Osteoarthritis (OA) is the principal cause of disability in the aging population, yet there are no successful pharmacological interventions which can reverse or prevent the degeneration of articular cartilage. Evidently, thorough understanding of the disease pathology at the cellular level is mandatory to develop disease-modifying drugs for OA. This dissertation is aimed at understanding the role of various biochemical factors involved in the pathogenesis of OA and targeting them to develop novel interventions. Towards achieving this goal, my first approach show that the controlled release of a heparan sulfate binding growth factor, Bone Morphogenetic Protein 2 (BMP2), using perlecan-modified biomaterials can induce anabolic changes in cartilage of mice with early OA. As the growth factor therapy becomes ineffective in the later stages of OA and since the clinical manifestation and diagnosis of OA mostly occurs late when the patients develop pain, my next approach was to target the subchondral bone changes in early OA. Recent work showed that mechanotransduction in bone is partially mediated through voltage-sensitive calcium channel (VSCC) and mice deficient in Cav3.2, the pore forming subunit of T-VSCC have reduced response to mechanical loading and decreased bone remodeling properties. I used this Cav3.2 T-VSCC knockout (KO) mouse to demonstrate that reduced mechanosensitivity in subchondral bone is beneficial in preventing load-induced OA. I demonstrate that mechanotransduction from osteoblasts via T-VSCC induces local metabolite secretion that stimulates osteoarthritic changes in chondrocytes and propose that targeting calcium channels in joints would slow/prevent progression of OA. Next, I identify leptin as one of the subchondral bone-derived catabolic factors expressed by the mechanically stimulated osteoblasts and I explore the therapeutic potential of inhibiting osteoblast-derived leptin activity in a post-traumatic mouse model of OA. Through this dissertation work I demonstrate novel potential targets and therapeutics that can be used at early and later stages of OA. With the rapid climb in the life expectancy and the associated increase in OA prevalence, clinical application of these strategies can help improve the quality of life in OA patients and reduce the heath care expenditure associated with knee replacement surgeries.
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