As of 2020, an estimated 654.1 million adults live with knee osteoarthritis (KOA) worldwide. Notably, women who are post-menopausal have higher incidence and severity of KOA compared to men. Despite this disproportionate effect on women, most KOA animal models include only males. In the few studies examining sex-differences, female mice paradoxically develop less severe KOA than males. One reason for this discrepancy may be that rodents spontaneously rejuvenate their ovarian follicles in middle-age and do not demonstrate a menopausal phenotype. In our lab, we have developed a novel, chemically induced menopause model that demonstrates more severe KOA than age-matched controls, suggesting that menopause may play a role in the pathogenesis of KOA. We are currently performing studies outlining the mechanisms that may be mediating menopause-induced KOA using histology, mass spectrometry proteomics, and network medicine analyses.

Correlative to the lack of studies examining menopausal effects on KOA, there are no disease-modifying treatments for menopause-associated KOA. For other menopausal diseases, hormone therapy (HT) is the most effective treatment. When given early in menopause, HT offers protective effects against some sex-hormone sensitive diseases, such as cardiovascular disease, and decreases the incidence of menopause-related symptoms, such as vaginal dryness. However, when HT is given late in menopause, some of these effects are the opposite, with risk of thromboembolism, dementia, and cardiovascular disease increased. This observation is typically explained by the “timing hypothesis”. The timing hypothesis suggests that if HT is given early in menopause, it exerts protective effects against sex-hormone sensitive diseases, while if started later in menopause, pathologic effects are observed. These effects seem to be tissue specific: cardiovascular disease and dementia are affected by this timing effect, while osteoporosis and uterine cancer are not. When looking at the possibility of this effect occurring in cartilage, we found in our mathematical modeling work that estrogen treatment given “early” after ovariectomy resulted in beneficial effects on cartilage integrity while treatment started “late” resulted in no such effects. In another arm of this project, we are testing the timing hypothesis in estrogen treatment and HT for KOA and exploring mechanisms that may be mediating the observed beneficial effects.

Lastly, given that the use of HT in women 10+ years beyond the onset of menopause is limited due to increased risk of adverse events and that HT outcomes in humans are, we are also exploring other alternatives for therapeutics, including synthetic biology techniques. Synthetic biology as a field aims to engineer new biological systems or redesign existing ones to optimize performance. One tool often employed for therapeutics is the synthetic circuit, which acts as a biological controls system. Feedback loops between artificially introduced promoter elements from synthetic circuits can enable modifiable control of pathway coupling, or even reverse the direction of effect. As such, we are currently designing a genetic circuit to re-frame how loss of estradiol affects genes of interest (GOI) and ultimately chondrocyte integrity in vitro.