TY  - JOUR
T1  - Metabolic Stress Accelerates Dysregulated Synovial Macrophage-Fibroblast Communication and Htra1 Overproduction in Osteoarthritis
JF  - bioRxiv
DO  - 10.1101/2024.09.26.615231
SP  - 2024.09.26.615231
AU  - Blackler, Garth
AU  - Klapak, Joseph
AU  - Guo, Qinli
AU  - Philpott, Holly T.
AU  - Jiang, HanYu
AU  - Ocica, Dariana
AU  - Del Sordo, Luigi
AU  - Fiset, Benoit
AU  - Walsh, Logan A.
AU  - Appleton, Christopher Thomas
AU  - ,
Y1  - 2024/01/01
UR  - http://biorxiv.org/content/early/2024/09/29/2024.09.26.615231.abstract
N2  - Biomechanical and metabolic factors increase the risk for osteoarthritis (OA) by causing supraphysiological stresses on joint tissues. Chronic exposure to these stresses contributes to failure of the joint organ system, resulting in pain and loss of function for patients with OA. The synovium is vital for joint organ health but during OA, synovial inflammation and damage are associated with worse outcomes including pain. Unfortunately, the separate and combined effects of metabolic and biomechanical stresses on synovial tissues are not well understood. In this study, metabolic syndrome (MetS) was associated with worse knee pain in patients with early-stage knee OA, suggesting that metabolic stress may act on synovial tissues during early-stage OA, exacerbating outcomes. In a rat model of experimental knee OA, the combined effects of biomechanical and metabolic stresses induced worse knee pain, cartilage damage, and synovial inflammation than biomechanical stress alone. Further, single-cell RNA sequencing of synovial macrophages and fibroblasts identified earlier metabolic (glycolytic and respiratory) shifts, neurogenesis, dysregulated communication, and cell activation when metabolic and biomechanical stresses were combined. Lastly, using a direct contact co-culture system, we showed that metabolic stress alters macrophage-fibroblast communication leading to increased expression of Htra1, a pathogenic protease in OA. This study identifies novel mechanisms that may represent amenable therapeutic targets for patients experiencing MetS and OA.Competing Interest StatementCTA is a consultant for Abbvie, Amgen, Bristol Myers Squibb, Celgene, Fresenius Kabi, Gilead, Janssen, Merck, Novartis, Pfizer, Hoffmaan LaRoche, Sandoz, Sanofi-Genzyme, and UCB.
ER  -