Abstract

Osteoarthritis (OA) may result from impaired ability of synovial macrophages to resolve joint inflammation. Increasing macrophage counts in inflamed joints through injection with bone marrow mononuclear cells (BMNC) induces lasting resolution of synovial inflammation. To uncover mechanisms by which BMNC may affect resolution, in this study, differential transcriptional signatures of BMNC in response to normal (SF) and inflamed synovial fluid (ISF) were analyzed. We demonstrate the temporal behavior of co-expressed gene networks associated with traits from related in vivo and in vitro studies. We also identified activated and inhibited signaling pathways and upstream regulators, further determining their protein expression in the synovium of inflamed joints treated with BMNC or DPBS controls. BMNC responded to ISF with an early pro-inflammatory response characterized by a short spike in the expression of a NF-ƙB- and mitogen-related gene network. This response was associated with sustained increased expression of two gene networks comprising known drivers of resolution (IL-10, IGF-1, PPARG, isoprenoid biosynthesis). These networks were common to SF and ISF, but more highly expressed in ISF. Most highly activated pathways in ISF included the mevalonate pathway and PPAR-γ signaling, with pro-resolving functional annotations that improve mitochondrial metabolism and deactivate NF-ƙB signaling. Lower expression of mevalonate kinase and phospho-PPARγ in synovium from inflamed joints treated with BMNC, and equivalent IL-1β staining between BMNC- and DPBS-treated joints, associates with accomplished resolution in BMNC-treated joints and emphasize the intricate balance of pro- and anti-inflammatory mechanisms required for resolution. Combined, our data suggest that BMNC-mediated resolution is characterized by constitutively expressed homeostatic mechanisms, whose expression are enhanced following inflammatory stimulus. These mechanisms translate into macrophage proliferation optimizing their capacity to counteract inflammatory damage and improving their general and mitochondrial metabolism to endure oxidative stress while driving tissue repair. Such effect is largely achieved through the synthesis of several lipids that mediate recovery of homeostasis. Our study reveals candidate mechanisms by which BMNC provide lasting improvement in patients with OA and suggests further investigation on the effects of PPAR-γ signaling enhancement for the treatment of arthritic conditions.

Highlights

  • Osteoarthritis (OA) is a common and debilitating condition that affects horses and people [1, 2]

  • Our current data suggest that bone marrow mononuclear cells (BMNC)-derived mechanisms of resolution are primarily represented by constitutively expressed homeostatic mechanisms, whose expression is enhanced to counteract tissue damage

  • These homeostatic mechanisms translate into macrophage proliferation, enlarging the “macrophage army” to fight aggressors, improving their general and mitochondrial metabolism to better resist the challenges of inflammatory oxidative stress

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Summary

Introduction

Osteoarthritis (OA) is a common and debilitating condition that affects horses and people [1, 2]. The recruitment of macrophages and the production of pro-resolving mediators is triggered by enzymes synthesized during the acute inflammatory process [13]. Macrophages play such a fundamental role in resolving inflammation and promoting tissue repair that impaired macrophage chemotaxis and/or macrophage depletion results in inefficient healing or chronic inflammation [14,15,16]. Blocking acute inflammation with anti-inflammatory medications interferes, at least to some degree, with macrophage recruitment and the pro-resolving response, and often prevents effective resolution and recovery of homeostasis [12, 13]. Targeted therapies for chronic joint inflammation should have pro-resolving properties, which precisely combine pro- and antiinflammatory mechanisms [12]

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