Targeting Pathological Angiogenesis after Joint Injury

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ABSTRACT INVESTIGATORS: Tristan Maerz, PhD (PI) is a biomedical engineer and early-stage investigator focused on joint injury and post-traumatic osteoarthritis (PTOA). Andrea Alford, PhD (Co-PI) is a matrix biologist focused on the interactions of matricellular proteins, the extracellular matrix, and cells. Together, they have extensive complementary expertise to study the role of thrombospondin-2 in PTOA using innovative methodologies. RESEARCH CONTEXT: PTOA accounts for ~12% of osteoarthritis cases, constituting ~5.6 million sympto- matic cases in the US. Synovitis is now increasingly recognized as a perpetuator of joint degeneration, analo- gous to its role in rheumatic diseases. Alongside inflammation is increased angiogenesis, which promotes in- flammation and tissue catabolism by increasing vascular access to inflammatory cells and cytokines within the joint. However, no study has demonstrated whether modulating the degree of angiogenesis affects intraarticu- lar inflammation and downstream PTOA severity after joint injury. Thrombospondin-2 (TSP2) is an endogenous anti-angiogenic factor, and this proposal’s preliminary data demonstrates that it is markedly upregulated in the synovium following joint injury, making it a potential regulator of intraarticular angiogenesis and PTOA. SPECIFIC AIMS: 1). Determine the extent to which temporal TSP2 knockout at the time of injury increases an- giogenesis, synovitis, and PTOA severity. 2). Assess the anti-angiogenic, anti-inflammatory, and PTOA-miti- gating effect of intraarticular TSP2 gene transfer. RESEARCH PLAN: In Aim 1, single-cell RNAseq will be used to profile TSP2(+) synovial cell populations and associated angiogenic pathways. A global, inducible Rosa26-CreERT2;TSP2flox mouse will then be used to ab- late TSP2 to assess the extent to which increased intraarticular angiogenesis affects synovitis, matrix metallo- proteinase (MMP) activity (assessed using molecular imaging), pain and function, and histological and imag- ing-based PTOA severity. In Aim 2, adenoviral TSP2 will be administered intraarticularly to both WT and Rosa26-CreERT2;TSP2flox mice after joint injury, and the downstream effect on intraarticular angiogenesis, synovitis, MMP activity, pain and function, chondrocyte hypertrophy, and PTOA severity will be assessed to elucidate whether TSP2 can be employed as a disease-modifying therapeutic. INNOVATION: Demonstrating a relationship between the degree of post-injury angiogenesis and PTOA sever- ity would be a high-impact finding by identifying a potentially-modifiable acute process that affects PTOA path- ogenesis. While TSP2’s anti-angiogenic role has been studied extensively in fracture healing, little to no litera- ture has elucidated its role in the synovium and in the context of PTOA. Lastly, this proposal aims to use sev- eral innovative imaging methodologies to characterize joint catabolism and PTOA severity, providing a poten- tial translational path for earlier, more sensitive PTOA and OA diagnosis using innovative imaging.