Menopausal Knee-ds: Elucidating mechanisms and treatments for knee osteoarthritis

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PROJECT SUMMARY/ABSTRACT Background: As of 2020, an estimated 654.1 million adults live with knee osteoarthritis (KOA), and women who are post-menopausal are nearly twice as likely to develop KOA compared to men. Despite this, most animal studies on KOA include only males, and, of the few studies utilizing females, menopause is typically not included, as it is not a naturally occurring process in non-primates. As such, there is a paucity of literature aimed at understanding mechanisms of menopause associated KOA and a corresponding absence of treatment interventions specifically for post-menopausal people with KOA. As a part of my PhD work thus far, I have developed a chemically-induced menopause model by injecting middle-aged female mice with 4- vinylcyclohexene diepoxide (VCD). I have confirmed this model displays a menopausal phenotype, including perimenopause, and that these mice display more severe KOA than age-matched, non-menopausal mice. The research goals of this fellowship are to interrogate mechanisms of menopause-induced KOA using our VCD model (Specific Aim 1) and employ synthetic biology techniques to lay the groundwork for new treatment modalities for menopause-indued KOA and (Specific Aim 2). Specific Aim 1: A component of E3 ubiquitin ligase was recently identified in a GWAS meta-analysis as a unique contributor to OA in women. As such, I will interrogate the role of estradiol-regulated, ubiquitin proteolysis in mediating menopause-induced KOA using our VCD menopause model. Changes in ubiquitin proteolysis signaling across perimenopause, menopause, and with estradiol treatment will be quantified both in vivo and in vitro. We hypothesize that (1) menopause induction will disrupt ubiquitin proteolysis activity and (2) estradiol treatment started early in menopause will restore ubiquitin proteolysis signaling and ultimately quinch menopausal KOA. Specific Aim 2: I will design an estradiol-regulated controls circuit to modulate a gene of interest (GOI) in vitro. A significant drop in estradiol is a principal physiological change associated with menopause, and an estradiol- repressed promoter will be designed to turn the circuit on. GOI candidates will be generated from previous studies and will be systematically tested to determine ideality for mediating chondrogenicity. We hypothesize that a genetic controls circuit modulated by estradiol will attenuate chondrocyte health in vitro. Impact: To support my fellowship, I have assembled a multidisciplinary team with expertise in KOA, menopause, aging, and synthetic biology. I have strategized with my mentoring team to design a rigorous training plan that will take advantage of the extraordinary research environments offered at my sponsor’s new institution (Spaulding Rehabilitation, Harvard Medical School) and the University of Pittsburgh, where I remain a full-time student. This fellowship will propel me towards my long-term goals of being a physician-scientist who practices orthopedic surgery and research leader in joint diseases and injuries presenting in women.