Regulators of Joint Inflammation, Nociception, and Synovial Biology in Post-Traumatic Osteoarthritis

Abstract

The global burden of osteoarthritis (OA) and post-traumatic osteoarthritis (PTOA) ranks among the most significant challenges in musculoskeletal health. With estimated prevalence affecting approximately 595 million individuals globally as of 2020, the burden of OA, including economic, psychosocial, and quality of life impacts, demands urgent therapeutic advancements. This doctoral thesis employs a clinically relevant, noninvasive anterior cruciate ligament rupture (ACLR) mouse model of PTOA to investigate regulators of joint inflammation, nociception, and synovial biology in PTOA, with the goal of identifying promising targets for future therapeutic intervention.

Aim 1: “Sex differences in murine PTOA”. Aim 1 comprehensively characterizes biological sex differences in murine PTOA progression, establishing a critical foundation for the subsequent studies in this body of work. This study reveals that male mice suffer from more severe joint damage and persistent synovitis compared to females. Notably, female mice exhibit resolution of synovial inflammation over time, highlighting sex-based biological differences in murine PTOA pathophysiology.

Aim 2A: “The role of thrombospondin-2 (TSP2) in PTOA part I: Lessons from the TSP2-null mouse”. Aim 2A examines the role of thrombospondin-2 (TSP2) in maintaining joint homeostasis and its implications for PTOA. TSP2-null mice demonstrate increased idiopathic OA and synovitis severity, implicating TSP2 as a crucial regulator of joint homeostasis and underscoring the need for more precise targeting of TSP2 in order to leverage TSP2 signaling as a treatment for PTOA.

Aim 2B: “The role of thrombospondin-2 (TSP2) in PTOA part II: Lessons from the inducible TSP2-KO mouse”. Aim 2B evaluates the effects of inducible TSP2 ablation at the time of joint injury on PTOA. By employing an inducible knockout approach, this study avoids the developmental confounders introduced by the complete TSP2-null mouse in Aim 2A. The results of this aim highlight a critical window during the early inflammatory phase where TSP2-targeted therapies could effectively mitigate PTOA progression.

Aim 3: “The role of chemokine ligand-16 (CXCL16) in joint pain and inflammation”. Aim 3 explores the CXCL16-CXCR6 axis as a novel target in addressing joint pain and inflammation. The study elucidates the role of CXCL16 as a pro-inflammatory pathway and nociceptive signaling activator in the joint. By utilizing the CXCR6 antagonist, ML339, these studies identified a novel role for the CXCL16-CXCR6 signaling mechanism in driving nociceptive signaling and nocifensive behaviors.

Together, the studies presented herein advance the understanding of sex-specific, molecular, and cellular processes in PTOA, proposing new therapeutic targets and strategies that could improve clinical outcomes and quality of life for the millions of vulnerable people affected by PTOA worldwide.