Regulation of sex dimorphism in osteoarthritis through stress microRNA and Hedgehog signaling

Brown University, Providence RI

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Abstract

Osteoarthritis (OA) is a degenerative joint disease involving articular cartilage degradation, chronic inflammation, and bone remodeling. Although it is a leading cause of disability in the elderly, there is no FDA approved disease modifying osteoarthritis drugs (DMOADs) currently. There is a striking disparity of OA pathogenesis between women and men. The World Health Organization (WHO) Global Health Estimates estimated the death/disability rate for musculoskeletal disorders is about 65% in women and 30% in men. Women had a higher prevalence of knee OA, increasing dramatically around the time of menopause and experiencing more debilitating pain than men. The reasons for the sex difference are not yet completely clear, but the understanding of how and why OA occurs differently in women and men is crucial for developing effective personalized treatment. We have previously identified a mechano-sensitive microRNA, miR-365, which activates under stress and inflammation to accelerate OA onset and progression. Using a miR-365 transgenic (Tg) mouse model generated from our lab, we found that male and female responded differently to miR- 365 activation with female more susceptible to OA. The accumulation of senescence-associated secretory phenotype (SASPs) associated with aging-OA can be reduced by a FDA-approved nucleoside reverse transcriptase inhibitor (NRTI) lamivudine (3TC) in the OA mice. Thus, NRTI may provide a good drug candidate to treat aging-associated OA. We hypothesize that this sex dimorphism is related to the sex-specific regulation in the hedgehog (HH) signaling as HH interacting protein (HHIP) is a direct target of miR-365. HH has been shown as a main signal activating OA in the literature. Our preliminary results showed sex-differences in HH signaling ligands (IHH), receptors (PTCH, SMO), and downstream targets (GLI) between male and female patients and miR-365 Tg mice. The scientific goal of this project is to determine how sex-specific differences contribute to OA pathogenesis and drug treatments through the regulation of stress microRNA miR-365 and HH signaling using male and female miR mice. This will be tested through three aims. Aim 1: Identify gene expression patterns of HH signaling in different senescent cell populations in miR-365 Tg mice by performing single-cell RNA sequencing (scRNAseq). It will establish comprehensive understandings of how HH and other signaling pathways vary between different OA cell clusters in a sex-specific manner, and how their transition and interaction contribute to OA pathogenesis. Aim 2: Determine the cellular pattern of HH signaling by performing spatial transcriptomics analysis of OA cartilage in male and female miR-365 Tg mice. It will offer detailed spatial information of HH signaling in cartilage cells including chondrocytes, mesenchymal stromal cells (MSCs), and senescent MSCs, and how changes in their distribution correspond to sex-difference in local signaling and OA severity between male and female miR mice. Aim 3: Distinguish the differential effects of NRTI treatment on OA onset and progression through HH signaling by scRNAseq and spatial transcriptomics analysis during different time points of OA pathogenesis in miR-365 Tg mice. This allows for evaluation of early and late 3TC treatments in ameliorating OA phenotypes, inhibiting HH signaling and other OA signaling pathways, and developing sec-specific treatments for OA.