Investigation of periostin and lubricin in knee osteoarthritis and pain in humans, dogs, and rodents
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The overarching goal of this work is to advance knowledge of the structural and pain outcomes of knee osteoarthritis (OA), a degenerative joint disease characterized by pain and loss of function that affects millions worldwide, in naturally occurring and induced animal models. The introductory chapter covers essential background for understanding the purpose and methods of the later works. The second chapter describes protein targets, detected using proteomics, in dog and human knee joint fluid after spontaneous anterior cruciate ligament (ACL) injury. The most upregulated protein in both species, periostin, is associated with fibrosis in other diseases and may contribute to joint fibrosis and OA progression. Another protein of interest, highly upregulated in joint fluid from dogs with ACL injury, is lubricin. Lubricin is an endogenous synovial fluid proteoglycan with both anti-inflammatory and anti-adhesive properties. The third chapter discusses the chondroprotective effects of a bioengineered lubricin-inspired recombinant glycoprotein after intra-articular injection in male rats undergoing surgical ACL transection. In this chapter, advanced structural damage and pain responses are documented in female rats, whereas male rats demonstrated milder structural changes without detectable pain responses. Female sex is a prominent risk factor in human OA, yet most preclinical studies are performed exclusively in male animals, motivating greater understanding of sex differences in preclinical animal models. With the challenges in quantifying pain in humans and animals and the lack of correlation between structural OA changes and pain in humans, identifying animal models of both sexes that accurately capture both pain and structural changes in OA is difficult. The fourth chapter of this work seeks to describe pain responses and structural OA in three common induced mouse models of knee OA. Based on this framework, preliminary investigations into the effects of periostin loss-of-function on murine pain responses after OA induction are discussed in Appendix 2. The fifth and final chapter summarizes the overall findings and significance of the work described, highlighting areas of interest for future study.