Synovial inflammation in osteoarthritis progression

Sánchez-López, Elsa; Coras, Roxana; Torres, Alyssa; Lane, Nancy E.; Gumá, Mónica

doi:10.1038/s41584-022-00749-9

Cited by 439 publications

(291 citation statements)

References 259 publications

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“…Profound injury-induced changes in both proportion and abundance of subsets occurred by 7d ACLR; all clusters expanded numerically post-injury but the most robust increases were evident in subsets absent from healthy synovium – the αSMA+ and Sox9+ clusters (Figure 2E-G). Notably, the abundance of all subsets diminished by 28d ACLR, apart from Prg4 hi lining SFs, consistent with persistent lining hyperplasia observed in human PTOA(28, 29). Having defined distinct SF clusters and their temporal abundance, we assessed whether their unique transcriptomic profiles underpinned distinct functional roles.…”

Section: Resultssupporting

confidence: 79%

Synovial fibroblasts assume distinct functional identities and secrete R-spondin 2 to drive osteoarthritis

Knights

Farrell

Ellis

et al. 2022

Preprint

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ObjectivesSynovium is acutely affected following joint trauma and contributes to post-traumatic osteoarthritis (PTOA) progression. Little is known about discrete cell types and molecular mechanisms in PTOA synovium. We aimed to describe synovial cell populations and their dynamics in PTOA, with a focus on fibroblasts. We also sought to define mechanisms of synovial Wnt/β-catenin signaling, given its emerging importance in arthritis.MethodsWe subjected mice to non-invasive anterior cruciate ligament rupture as a model of human joint injury. We performed single-cell RNA-sequencing to assess synovial cell populations, subjected Wnt-GFP reporter mice to joint injury to study Wnt-active cells, and performed intra-articular injections of the Wnt agonist R-spondin 2 (Rspo2) to assess whether gain-of-function induced pathologies characteristic of PTOA. Lastly, we used cultured fibroblasts, macrophages, and chondrocytes to study how Rspo2 orchestrates crosstalk between joint cell types.ResultsWe uncovered seven distinct functional subsets of synovial fibroblasts in healthy and injured synovium, and defined their temporal dynamics in early and established PTOA. Wnt/β-catenin signaling was overactive in PTOA synovium, and Rspo2 was strongly induced after injury and secreted exclusively by Prg4hi lining fibroblasts. Trajectory analyses predicted that Prg4hi lining fibroblasts arise from a pool of Dpp4+ mesenchymal progenitors in synovium, with SOX5 identified as a potential regulator of this emergence. We also showed that Rspo2 orchestrated pathological crosstalk between synovial fibroblasts, macrophages, and chondrocytes.ConclusionsSynovial fibroblasts assume distinct functional identities during PTOA, and Prg4hi lining fibroblasts secrete the Wnt agonist Rspo2 to drive pathological crosstalk in the joint after injury.

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Section: Resultssupporting

confidence: 79%

Synovial fibroblasts assume distinct functional identities and secrete R-spondin 2 to drive osteoarthritis

Knights

Farrell

Ellis

et al. 2022

Preprint

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“…The inflammatory microenvironment of the OA joint is found to be orchestrated by macrophages, neutrophils, and multiple inflammatory cytokines. Previous studies have demonstrated the importance of macrophages and neutrophils in driving inflammatory and destructive responses in OA ( 32 , 33 ). These results indicated there is a triggering low-grade inflammatory cycle that leads to the infiltration of macrophages and neutrophils and further induce structural changes in the synovial tissues of OA rats.…”

Section: Discussionmentioning

confidence: 98%

Innate/Inflammatory Bioregulation of Surfactant Protein D Alleviates Rat Osteoarthritis by Inhibiting Toll-Like Receptor 4 Signaling

Jiang

Zhang

et al. 2022

Front. Immunol.

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Osteoarthritis (OA) is a deteriorating disease of cartilage tissues mainly characterized as low-grade inflammation of the joint. Innate immune molecule surfactant protein D (SP-D) is a member of collectin family of collagenous Ca2+-dependent defense lectins and plays a vital role in the inflammatory and innate immune responses. The present study investigated the SP-D-mediated innate/inflammatory bioregulation in OA and explored the underlying molecular mechanism. Transcriptome analysis revealed that SP-D regulated genes were strongly enriched in the inflammatory response, immune response, cellular response to lipopolysaccharide (LPS), PI3K-Akt signaling, Toll-like receptor (TLR) signaling, and extracellular matrix (ECM)-receptor interaction pathways. Knockdown of the SP-D gene by the recombinant adeno-associated virus promoted the macrophage specific markers of CD68, F4/80 and TLR4 in the articular cartilage in vivo. SP-D alleviated the infiltration of synovial macrophages and neutrophils, and inhibited TLR4, TNF-α and the phosphorylation of PI3K, Akt and NF-κB p65 in cartilage. SP-D suppressed cartilage degeneration, inflammatory and immune responses in the rat OA model, whilst TAK-242 strengthened this improvement. In in vitro conditions, SP-D pre-treatment inhibited LPS-induced overproduction of inflammation-correlated cytokines such as IL-1β and TNF-α, and suppressed the overexpression of TLR4, MD-2 and NLRP3. SP-D prevented the LPS-induced degradation of ECM by down-regulating MMP-13 and up-regulating collagen II. Blocking of TLR4 by TAK-242 further enhanced these manifestations. We also demonstrated that SP-D binds to the TLR4/MD-2 complex to suppress TLR4-mediated PI3K/Akt and NF-κB signaling activation in chondrocytes. Taken together, these findings indicate that SP-D has chondroprotective properties dependent on TLR4-mediated PI3K/Akt and NF-κB signaling and that SP-D has an optimal bioregulatory effect on the inflammatory and innate responses in OA.

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“…Proinflammatory cytokines have an important role in OA joint destruction [ 8 , 37 ], promoting damage in joint extracellular matrices and stimulating the progression of OA [ 9 , 10 ]. High IL-1β and TNF-α levels upregulate proteolytic enzymes, such as MMPs and ADAMTS family, which degrade the extracellular matrix [ 9 , 11 ].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Effects of Live Lactobacillus plantarum GKD7 in a Rat Model of Knee Osteoarthritis

et al. 2022

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Osteoarthritis (OA) is a painful, progressive chronic inflammatory disease marked by cartilage destruction. Certain synovial inflammatory cytokines, such as IL-1β and TNF-α, promote OA inflammation and pain. Lactobacillus spp. is a well-known probiotic with anti-inflammatory, analgesic, antioxidant, and antiosteoporotic properties. This study evaluated the therapeutic effects of a live L. plantarum strain (GKD7) in the anterior cruciate ligament transection (ACLT)-induced OA rat model. The results show that oral administration of live L. plantarum GKD7 improved weight-bearing asymmetry after ACLT surgery. Moreover, micro-computed tomography images and histopathological analysis show that oral live L. plantarum GKD7 improved subchondral bone architecture, protected articular cartilage against ACLT-induced damage, and reduced synovial inflammation. L. plantarum GKD7 also reduced IL-1β and TNF-α production in OA cartilage and synovium. Thus, orally administered live L. plantarum GKD7 appears to effectively slow the progression of OA.

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Synovial inflammation in osteoarthritis progression

Cited by 439 publications

References 259 publications

Synovial fibroblasts assume distinct functional identities and secrete R-spondin 2 to drive osteoarthritis

Synovial fibroblasts assume distinct functional identities and secrete R-spondin 2 to drive osteoarthritis

Innate/Inflammatory Bioregulation of Surfactant Protein D Alleviates Rat Osteoarthritis by Inhibiting Toll-Like Receptor 4 Signaling

Therapeutic Effects of Live Lactobacillus plantarum GKD7 in a Rat Model of Knee Osteoarthritis

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