Impact of mast cell heterogeneity on Osteoarthritis

SUMMARY Osteoarthritis (OA) is a highly prevalent and debilitating disease, affecting over 27 million people in the US. Its risk factors include aging, joint injury, obesity, and the female sex. It is characterized by the degeneration of weightbearing joints, which is exacerbated by localized and persistent inflammation. However, there is not a

single FDA-approved disease-modifying treatment for OA, posing an urgent need for designing new treatment options. Typical anti-inflammatory therapies have not successfully halted OA progression in clinical trials, suggesting that perhaps OA has an inflammatory signature different from other types of arthritis and requires a

strategy to specifically target this signature. In this grant, we will address this critical need for the understanding the inflammatory milieu unique to OA. One of the predominant types of immune cells increased in human OA joints is the mast cell (MC). Mice deficient in MCs had diminished joint damage in injury-induced OA, suggesting that MCs are required for OA progression.

This notion is further supported by our gain-of-function data showing that promoting MC activity exacerbated joint damage, thus warranting mechanistic investigation of MCs in OA. One special feature of MCs is their capacity to store inflammatory mediators in their numerous granules. When stimulated, MCs release them over

time; and since MCs are long-lived, they also replenish these inflammatory mediators for future use. Thus, the MC is a strong candidate for sustaining chronic inflammation in OA. Another intriguing property of the MC is it demonstrates a level of heterogeneity that is altered under disease conditions and in a tissue-specific way. In

the synovium, there are two known subtypes, based on histological analysis of the two key proteases: (i) MCTC that expresses both chymase and tryptase and (ii) MCT that expresses only tryptase. While these two enzymes have their own substrates, the two subtypes also likely to differ in the expression of other genes. However, little

is known about the nature of MC heterogeneity in OA joints. Our central hypothesis is that MC heterogeneity constitutes a unique inflammatory signature of OA to promote OA pathogenesis. The objective of this grant is to investigate the genetic basis and functions of MCTC and MCT subtypes in the OA synovium, through performing

advanced proteomics and single cell RNAseq technologies as well as testing them in the mouse model of Anterior Cruciate Ligament Transection (ACLT). From this investigation, we will uncover a new level of regulation that may elucidate a key aspect of OA-specific inflammatory microenvironment and inspire the design of more effective strategies to target OA. Thus, this study

has the potential of being highly impactful and paradigm-changing for combating OA in our ever-aging society.