Considering that increasing age is a top risk factor for primary, or naturally occurring osteoarthritis (OA), an unmet need is that aging per se is not well studied in current OA models. Therefore, the mechanisms that cause the onset and early progression of age-related OA are incompletely understood and disease modifying therapies do not exist. Therefore, NOT-AG-19-037 was issued to ?accelerate the characterization of new or underutilized models? and ?test hypotheses that will lead to an improved understanding of the mechanisms of initiation and progression of OA.? Non-human primates are the closest evolutionary relative to humans and share many physiological and biological characteristics of human aging. The common marmoset is the smallest anthropoid primate with high potential for human translation and a lifespan amenable to studying mechanisms that initiate age-related disease. In young, male rodents, increased mTOR activity contributes to the onset of OA and inhibition of mTOR prevents injury-induced OA. However, it is not yet known if mTOR inhibition could slow the pathogenesis of naturally occurring OA that is prevalent in aging humans. Further, it is unknown if mTOR contributes to the pathogenesis of OA in females like in males. To resolve these gaps in knowledge, this proposal will pursue two specific aims.
In Aim 1, we test the effect of age on naturally occurring OA in the marmoset. For this aim, we will use marmoset samples from the San Antonio Nathan Shock Center to comprehensively evaluate OA in articular cartilage, subchondral bone, synovium and menisci by high-resolution micro-computed tomography, histopathology, and immunohistochemistry in cohorts of adult, old, and older marmosets. We will also evaluate if OA is accompanied with marmoset behavior and activity linked to pain, immobility, and mortality.
In Aim 2, we will test the hypothesis that mTOR inhibition by rapamycin will lower naturally occurring knee OA pathology and modify behavior linked to pain in both male and female marmosets. For this aim, we will leverage an ongoing lifespan study in marmosets treated with placebo or the mTOR inhibitor rapamycin. Samples will be collected at necropsy to evaluate OA pathology and mTOR inhibition in articular cartilage, subchondral bone, synovium and menisci. mTOR inhibition will be evaluated by measuring downstream protein and gene targets via IHC and RNA sequencing. By completion of this project it is expected that we will develop the marmoset as a novel translational model of naturally occurring age-related OA and that we will identify if mTOR and downstream pathways contribute to the etiology and treatment of naturally occurring OA. Establishing the marmoset as a model to identify exploitable mechanisms will in turn help facilitate the development of disease- modifying therapies for human OA.
Establishing the common marmoset as a model of age-related osteoarthritis that is prevalent in older humans and testing mechanisms that initiate naturally occurring osteoarthritis will help facilitate the development of disease modifying therapies for human OA.
