Our Work

Delineating Signals that Govern Interorgan Crosstalk in Osteoarthritis with Obesity and Aging

Osteoarthritis (OA) is the leading cause of musculoskeletal pain, which represents the primary driver for patient care-seeking behavior. There are presently no disease-modifying OA drugs, and existing pain management strategies are inadequate. Obesity is one of the leading co-morbidities in OA patients, and as such, our work has focused on better understanding this complicated relationship. We have shown that cartilage damage and pain with OA may originate from factors outside cartilage, or outside the knee joint, like signals from adipose tissue (fat). These studies were motivated by clinical and preclinical data that illustrate that changes in body mass with obesity and loading incompletely explain OA burden.

Organisms are comprised of complex, interconnected signaling networks of organs, tissues, and cells. With chronic disease, aging, and multimorbidity, this interorgan communication can break down, resulting in pathology. Our goal is to disentangle and understand interorgan crosstalk, as we believe this line of inquiry is the key to developing a first-in-class drug for OA. To this end, we use our interdisciplinary skillset to characterize crosstalk from systemic contributors to musculoskeletal (MSK) damage like fat, the gut microbiome, and circulating factors in blood. These interactions are critical to understanding the basic mechanisms of the disease and developing much-needed novel therapeutic strategies. We use novel transgenic, genetic, behavioral, and molecular tools through an integrative biology lens to disentangle adipocyte interorgan crosstalk with effector tissues like nerves and joint tissues in OA, metabolic dysfunction, and aging. We will harness these mechanistic insights to create a novel therapeutic strategy for OA with relevance to obesity, aging, and other chronic diseases.

The Role of Alternative Complement Signaling and Neuro-immune Metabolic Crosstalk in OA Pain 

Pain and structural damage can manifest in a discordant fashion yet preclinical models of OA have historically translated poorly in clinical trials, perhaps because they rely on structural indicators of cartilage and joint damage with few studies including pain or behavioral assessments in mice. There is a need to develop preclinical models of differential manifestations of pain and structural damage to represent OA hyperalgesia. To best understand pain susceptibility phenotypes in OA, identifying groups or models with low-pressure pain thresholds, or significantly increased hyperalgesia, has been suggested as a valuable strategy. We have identified a mouse model that displays discordant knee pain and structural damage which provides the unique opportunity to explore pain independently of structural damage (complement factor D knockout). Recent studies have identified that the dorsal root ganglia (DRGs) nerves play an important role in knee joint pain, and as such, we are studying the DRGs in this and other models of mouse OA to better understand the mechanisms of pain in OA. Moreover, the majority of OA patients are individuals with obesity, and clinical data suggest that these patients can experience more severe pain compared to non-obese OA patients. Therefore, for maximal impact, it is critical to consider therapeutic targets that are relevant to OA patients with and without obesity.

Supported generously by funding from: Arthritis National Research Foundation, NIH NIAMS Chicago Center on Musculoskeletal Pain (C-COMP P30)

The Role of Fat in Osteoarthritis


Our previous studies demonstrated that fat outside the joint, or adipose tissue, is a source of systemic inflammation involved in the pathogenesis of osteoarthritis (OA). However, the manner in which this occurs, and the factors involved, remain unclear. We have developed a platform to interchangeably and specifically delete signaling factors from fat to uncover the mechanism of adipose-cartilage signaling using genome engineering tools. This designer adipose implant lacks specific factors implicated in disease progression using induced pluripotent stem cells (iPSCs), which allows us to dissect the role of individual signals from fat in OA pathogenesis in a highly controlled manner to better understand the mechanisms of fat-cartilage crosstalk. Then, using this novel and flexible designer adipose tissue platform, we will hijack fat signaling to deliver anti-inflammatory mediators in a tunable and well-controlled manner, which will serve as the basis for a novel regenerative therapy for OA. Ultimately, this approach uses the cell’s own regulatory mechanisms to guide therapeutic delivery in response to inflammatory signals. This platform can be flexibly expanded to endogenously deliver a variety of biologic drugs, establishing a novel approach and cell-based therapy using iPSCs that can be differentiated into designer fat or other tissues.

Supported generously by funding from: NIH NIAMS K99/R00 Pathway to Independence Award