BCCMA: Targeting Osteoarthritis Pain and Progression: Defining biologic and inflammatory markers associated with rapid progression

1 Knee osteoarthritis (OA) is a leading cause of disability worldwide. Disease development in 2 Veterans occurs at significantly younger ages and at higher numbers than the population in 3 general. Currently there are no disease modifying anti-osteoarthritis drugs (DMOAD) due in part 4 to a historical focus on identification and tracking of radiographic OA outcomes rather than

5 cellular and molecular disease pathways in pre-radiographic OA. The TOPP Collaborative Merit 6 Review will test the central hypothesis that heterogeneity in OA pain and structural progression 7 is related to the “immune pathotype” of OA, which arises from the variability in the cellular and 8 molecular responses of bone, cartilage, and synovium to inflammation and joint mechanical

9 environment. The overarching Specific Aims are: Aim 1: To improve understanding of 10 osteoarthritis (OA) pathogenesis to enable development of targeted early treatment 11 approaches; and Aim 2: To establish preclinical and clinical data for new therapeutic targets to 12 reduce pain and prevent OA progression. Achieving these Aims requires the complementary

13 and synergistic expertise of our Collaborative Merit to employ early and late OA clinical cohorts 14 prevalent in the VAHCS and joint injury animal models to define the immune pathotypes of OA 15 and to test novel therapeutic approaches. This particular project will establish a cohort of 16 patients without significant signs of radiographic OA who suffer from symptomatic degenerative

17 meniscus tears (DMT) to identify predictors of pain and progression after arthroscopic partial 18 meniscectomy (APM). Degenerative meniscus tears (DMT) are prevalent starting in middle age 19 and can occur in the absence of significant radiographic knee OA. Growing evidence also 20 suggests that the DMT may signal transition of the knee to an OA phenotype. Similar to OA

21 treatment, clinical outcomes for DMT patients have been reported to be highly variable 22 irrespective of whether treatment is with physical therapy, APM, or sham surgery. We 23 hypothesize that the variable results following APM treatment of DMT are related to whether 24 joint biology has switched to an OA phenotype. This project aims to test this hypothesis by

25 identifying biological predictors of knee pain and structural progression in Veterans 2-years after 26 treatment of symptomatic DMT with APM. Aim 1 of this study will test if preoperative synovial 27 fluid levels of OA biomarkers supported by our preliminary data and prior work (C2C, C1,2C, 28 COMP and CS846) predict knee pain and structural progression in DMT patients 2-years

29 following APM. Aim 2 will test if preoperative serum biological markers implicated in OA pain by 30 our preliminary data (IL-4, IL-13, and IL-17E) predict knee pain and structural progression 2 31-years after APM. Aim 3 will test if preoperative levels of urine uCTXII and uCTXIIa predict knee 32 pain and structural progression in our DMT cohort 2-years after APM. Achieving the Aims of this

33 proposal will contribute new information important to defining immune pathotypes and 34 biomarkers of early human OA. Completing this project will also help determine whether DMT 35 patients with biological signatures of OA comprise a novel early OA cohort prevalent within the 36 VAHCS suitable for clinical trials evaluating new treatment strategies to prevent or delay the

37 onset of disabling OA. These outcomes support the overarching hypothesis and Aims of the 38 TOPP Collaborative Merit Review and have high potential to improve the care of the large 39 number of Veterans and members of the general public who suffer from knee OA.