UCSF

The infrapatellar fat pad (IFP) has gained considerable attention in research on knee osteoarthritis (OA) for its substantial inflammatory role in knee joint health beyond simple mechanical shock-absorption. Despite increased efforts to investigate the structure, a consensus on whether the IFP contributes a pro- or anti-inflammatory role is lacking. The IFP is a highly innervated structure that contains immune cells, which highlight the candidacy of the IFP to contribute to knee OA pain. However, minimal research has evaluated the relationship between the IFP and knee OA pain. Furthermore, despite evidence that the IFP demonstrates morphological and compositional changes based on BMI-derived obesity and sex in knee OA, investigation into the sensitivity of the IFP to such factors that relate to high-risk of knee OA and greater pain severity have yet to be explored. This dissertation leveraged multidisciplinary scientific approaches to investigate tissue abnormality at the IFP in relation to knee OA pain across sex and BMI and in response to a key signal involved in fat-cartilage crosstalk in OA. Magnetic resonance imaging (MRI) allows for accessible visualization of morphological tissue changes and was utilized to evaluate abnormality (e.g. inflammation and fibrosis) at the IFP in relation to pain. Greater tissue abnormality at the IFP was found to correlate with worse pain and symptoms in patients with isolated patellofemoral joint OA—a subpopulation of knee OA—and differ by sex and BMI, in that females and individuals with a BMI ≥30 kg/m2 demonstrated stronger relationships between the IFP and OA pain. Tissue profiling of the secreted factors from the IFP—termed secretome—revealed sex- and BMI-based differences in protein secretion that significantly correlated with patient-reported outcomes in patients with end-stage knee OA. These findings suggest that the state of the IFP (both through clinical and biological measures) may be related to OA pain, which has been historically challenging to understand given the well-described structure-pain discordance in knee OA. Furthermore, when the IFP secretome was probed with leptin (a key satiety hormone elevated in patients with obesity and females, correlates with pain, and mediates fat-cartilage crosstalk in knee OA degeneration), the IFP demonstrated dysregulation in factors involved in protein kinase signaling. Unlike cartilage and synovium, the IFP was the only tissue to show a unique modulation of leptin response in eicosanoids specifically by sex and BMI, which suggests a modulated pain profile with leptin. These findings are offer potential targets for therapeutic intervention of the IFP in knee OA. Differences in how the IFP relates to patient pain across sex and BMI provide an opportunity for patient stratification and prognostic insight into high-risk, high-pain knee OA populations. By connecting molecular, imaging, and clinical characteristics, the IFP may provide the ability to disentangle knee OA pain that has been previously difficult to unravel, and offers an untapped opportunity for precision care in high-risk, high-pain knee OA populations.