Reverse Engineering Adipose-Joint Interorgan Crosstalk in Osteoarthritis

Obesity-induced osteoarthritis (OA) involves both metabolic and biomechanical factors, and a key link is excess adipose tissue. To separate the mechanistic contributions of adiposity, we used a mouse model of lipodystrophy (LD), in which the animals completely lack fat but maintain normal body mass. Unexpectedly, we observed that LD mice are protected from cartilage damage. When fat was transplanted into LD mice, protection from OA was reversed, implicating that adipose tissue, and factors secreted by adipose tissue called adipokines – but not body weight – are critical mediators of joint degeneration. To determine which adipokines are involved in OA, we have developed a tissue engineering and regenerative medicine approach to generate designer fat pads that do not produce leptin, an adipokine widely associated with OA. By applying a multiomic approach that considers both the transcriptional landscape and the secretome of leptin KO fat pads and leveraging a novel proximity labeling approach for fat secreted factors, we can objectively determine which pathways and fat-secreted targets involved in the reintroduction of cartilage damage and importantly, pain, in mice. In patients, OA outcomes demonstrate sexual dimorphisms in both prevalence and symptoms, such that post-menopausal women with obesity are at exceptionally high risk for OA pain. We are also probing these dimorphic mechanisms in new models that separate the individual roles of chromosomal and gonadal sex in young and aged mice. Finally, we will discuss how we are targeting this mechanism in parallel by developing an induced pluripotent stem cell engineered anti-cytokine therapy, termed designer adipose tissue, using OA as a model.

Bio: Kelsey Collins is an assistant professor in the Departments of Orthopaedic Surgery and Anatomy at University of California San Francisco. Her lab is focused on defining novel mechanisms of interorgan crosstalk using osteoarthritis, obesity, aging, and knee pain as model systems in mice, cell models, and human tissues. They use bioengineering strategies to disentangle these interconnected factors in musculoskeletal disease and leverage these insights toward the development of a novel stem cell therapy that leverages metabolic promoters, like leptin, to drive engineered cell therapies.