Corrigendum: MSC therapy ameliorates experimental gouty arthritis hinting an early COX-2 induction.

[This corrects the article DOI: 10.3389/fimmu.2023.1193179.].

Effects of Tofacitinib on Muscle Remodeling in Experimental Rheumatoid Sarcopenia.

Sarcopenia is a frequent comorbidity of rheumatoid arthritis (RA). Clinical trials have shown that JAK inhibitors (JAKi) produce an asymptomatic increase in serum creatine kinase (CK) in RA, suggesting an impact on muscle. We evaluated the effect of JAKi in muscle remodeling in an experimental RA model. Antigen-induced arthritis (experimental RA, e-RA) was performed in 14 rabbits. Seven rabbits received tofacitinib (TOFA, orally 10 mg/kg/day). Animals were euthanized one day after the last ovalbumin injection, and muscles were prepared for histology, RT-PCR, and WB. C-reactive protein (CRP) and Myostatin (MSTN) serum concentration were determined by ELISA. Creatine and creatine kinase (CK) were analyzed. An increase in body weight as well as tibialis anterior cross-sectional area and diameter was observed in e-RA+TOFA vs. e-RA. e-RA decreased type II fibers and increased the myonuclei number, with all reverted by TOFA. TOFA did not modify CRP levels, neither did MSTN. TOFA significantly reduced IL-6, atrogin-1, and MuRF-1 compared with e-RA. e-RA+TOFA showed higher CK and lower creatine levels compared with e-RA. No differences in PAX-7 were found, while TOFA prevented the increase in MyoD1 in e-RA. Our model reflects the features of rheumatoid sarcopenia in RA. JAKi increased muscle mass through attenuating IL-6/JAK/STAT activation, decreasing atrogenes, and restoring muscle differentiation markers. These data together with an increase in CK support the role of CK as a valuable marker of muscle gain following JAKi treatment.

MSC therapy ameliorates experimental gouty arthritis hinting an early COX-2 induction.

Objective: The specific effect of Adipose-Derived Mesenchymal Stem Cells (Ad-MSC) on acute joint inflammation, where the response mostly depends on innate immunity activation, remains elusive. The pathogenesis of gouty arthritis, characterized by the deposition of monosodium urate (MSU) crystals in the joints, associated to acute flares, has been associated to NLRP3 inflammasome activation and subsequent amplification of the inflammatory response. Our aim was to study the effect of human Ad-MSC administration in the clinical inflammatory response of rabbits after MSU injection, and the molecular mechanisms involved. Methods: Ad-MSC were administered by intraarterial route shortly after intraarticular MSU crystal injections. Joint and systemic inflammation was sequentially studied, and the mechanisms involved in NLRP3 inflammasome activation, and the synthesis of inflammatory mediators were assessed in the synovial membranes 72h after insult. Ad-MSC and THP-1-derived macrophages stimulated with MSU were co-cultured in transwell system. Results: A single systemic dose of Ad-MSC accelerated the resolution of local and systemic inflammatory response. In the synovial membrane, Ad-MSC promoted alternatively M2 macrophage presence, inhibiting NLRP3 inflammasome and inducing the production of anti-inflammatory cytokines, such as IL-10 or TGF-ß, and decreasing nuclear factor-κB activity. Ad-MSC induced a net anti-inflammatory balance in MSU-stimulated THP-1 cells, with a higher increase in IL-10 and IDO expression than that observed for IL-1ß and TNF. Conclusion: Our in vivo and in vitro results showed that a single systemic dose of Ad-MSC decrease the intensity and duration of the inflammatory response by an early local COX-2 upregulation and PGE2 release. Ad-MSCs suppressed NF-kB activity, NLRP3 inflammasome, and promoted the presence of M2 alternative macrophages in the synovium. Therefore, this therapeutic approach could be considered as a pharmacological alternative in patients with comorbidities that preclude conventional treatment.

Purinergic System Signaling in Metainflammation-Associated Osteoarthritis.

Inflammation triggered by metabolic imbalance, also called metainflammation, is low-grade inflammation caused by the components involved in metabolic syndrome (MetS), including central obesity and impaired glucose tolerance. This phenomenon is mainly due to excess nutrients and energy, and it contributes to the pathogenesis of osteoarthritis (OA). OA is characterized by the progressive degeneration of articular cartilage, which suffers erosion and progressively becomes thinner. Purinergic signaling is involved in several physiological and pathological processes, such as cell proliferation in development and tissue regeneration, neurotransmission and inflammation. Adenosine and ATP receptors, and other members of the signaling pathway, such as AMP-activated protein kinase (AMPK), are involved in obesity, type 2 diabetes (T2D) and OA progression. In this review, we focus on purinergic regulation in osteoarthritic cartilage and how different components of MetS, such as obesity and T2D, modulate the purinergic system in OA. In that regard, we describe the critical role in this disease of receptors, such as adenosine A2A receptor (A2AR) and ATP P2X7 receptor. Finally, we also assess how nucleotides regulate the inflammasome in OA.