Synovial Fibrosis Involvement in Osteoarthritis

Zhang, Li; Xing, Runlin; Huang, Zhengquan; Ding, Liang; Li, Mingchao; Li, Xiaochen; Wang, Peimin; Mao, Jun J.

doi:10.3389/fmed.2021.684389

Cited by 42 publications

(42 citation statements)

References 88 publications

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“…Previously, it has been shown that GLS1 inhibition reduces the proliferation of RA synovial fibroblasts, and in vivo reduces joint swelling in a murine model of RA [ 20 ]. Furthermore, in myofibroblasts, GLS1 inhibition reduced ECM production [ 33 , 34 ], a feature of synovial fibrosis in both OA [ 35 , 36 , 37 ] and RA [ 38 ] disease. Importantly, our identification of glutamine–glutamate metabolism as a clinical feature that is enriched in obese OA patient synovial fluid (a patient cohort that exhibits greater levels of inflammatory cytokines), which suggests that targeting this particular metabolic pathway will be of clinical relevance.…”

Section: Discussionmentioning

confidence: 99%

Differential Metabotypes in Synovial Fibroblasts and Synovial Fluid in Hip Osteoarthritis Patients Support Inflammatory Responses

Farah

Wijesinghe

Nicholson

et al. 2022

IJMS

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Changes in cellular metabolism have been implicated in mediating the activated fibroblast phenotype in a number of chronic inflammatory disorders, including pulmonary fibrosis, renal disease and rheumatoid arthritis. The aim of this study was therefore to characterise the metabolic profile of synovial joint fluid and synovial fibroblasts under both basal and inflammatory conditions in a cohort of obese and normal-weight hip OA patients. Furthermore, we sought to ascertain whether modulation of a metabolic pathway in OA synovial fibroblasts could alter their inflammatory activity. Synovium and synovial fluid was obtained from hip OA patients, who were either of normal-weight or obese and were undergoing elective joint replacement surgery. The synovial fluid metabolome was determined by 1H NMR spectroscopy. The metabolic profile of isolated synovial fibroblasts in vitro was characterised by lactate secretion, oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) using the Seahorse XF Analyser. The effects of a small molecule pharmacological inhibitor and siRNA targeted at glutaminase-1 (GLS1) were assessed to probe the role of glutamine metabolism in OA synovial fibroblast function. Obese OA patient synovial fluid (n = 5) exhibited a different metabotype, compared to normal-weight patient fluid (n = 6), with significantly increased levels of 1, 3-dimethylurate, N-Nitrosodimethylamine, succinate, tyrosine, pyruvate, glucose, glycine and lactate, and enrichment of the glutamine–glutamate metabolic pathway, which correlated with increasing adiposity. In vitro, isolated obese OA fibroblasts exhibited greater basal lactate secretion and aerobic glycolysis, and increased mitochondrial respiration when stimulated with pro-inflammatory cytokine TNFα, compared to fibroblasts from normal-weight patients. Inhibition of GLS1 attenuated the TNFα-induced expression and secretion of IL-6 in OA synovial fibroblasts. These findings suggest that altered cellular metabolism underpins the inflammatory phenotype of OA fibroblasts, and that targeted inhibition of glutamine–glutamate metabolism may provide a route to reducing the pathological effects of joint inflammation in OA patients who are obese.

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Section: Discussionmentioning

confidence: 99%

Differential Metabotypes in Synovial Fibroblasts and Synovial Fluid in Hip Osteoarthritis Patients Support Inflammatory Responses

Farah

Wijesinghe

Nicholson

et al. 2022

IJMS

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“…When IL-1β and TNF-α bind to their receptors, an inflammatory signaling cascade is activated, which enhances inflammation and catabolism by increasing the expression of adhesion molecules [ 12 ]. The increased synthesis of cytokines, as well as increased expression of MMP’s family enzymes, can result in ECM degradation [ 13 ]. IL-1β associates with Th17 and NK22 cells for neutrophils recruitment into the tissue, which helps to promote OA [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Carnosine Alleviates Knee Osteoarthritis and Promotes Synoviocyte Protection via Activating the Nrf2/HO-1 Signaling Pathway: An In-Vivo and In-Vitro Study

et al. 2022

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The most common joint disease in the elderly is knee osteoarthritis (OA). It is distinguished by cartilage degradation, subchondral bone loss, and a decrease in joint space. We studied the effects of carnosine (CA) on knee OA in male Wistar rats. OA is induced by anterior cruciate ligament transection combined with medial meniscectomy (ACLT+MMx) method and in vitro studies are conducted in fibroblast-like synoviocyte cells (FLS). The pain was assessed using weight-bearing and paw-withdrawal tests. CA supplementation significantly reduced pain. The enzyme-linked immunosorbent assay (ELISA) method was used to detect inflammatory proteins in the blood and intra-articular synovial fluid (IASF), and CA reduced the levels of inflammatory proteins. Histopathological studies were performed on knee-tissue samples using toluidine blue and hematoxylin and eosin (H and E) assays. CA treatment improved synovial protection and decreased cartilage degradation while decreasing zonal depth lesions. Furthermore, Western blotting studies revealed that the CA-treated group activated nuclear factor erythroid 2-related factor (Nrf2) and heme oxygenase (HO-1) and reduced the expression of cyclooxygenase-2 (COX-2). FLS cells were isolated from the knee joints and treated with IL-1β to stimulate the inflammatory response and increase reactive oxygen species (ROS). The matrix metalloproteinase protein (MMP’s) levels (MMP-3, and MMP-13) were determined using the reverse transcription-polymerase chain reaction (RT-PCR), and CA treatment reduced the MMP’s expression levels. When tested using the 2′,7′-dicholorodihydrofluroscene diacetate (DCFDA) assay and the 5,5′,6,6′-tetracholoro-1,1′,3,3′-tertraethylbenzimidazolcarboc janine iodide (JC-1) assay in augmented ROS FLS cells, CA reduced the ROS levels and improved the mitochondrial membrane permeability. This study’s investigation suggests that CA significantly alleviates knee OA both in vitro and in vivo.

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“…Synovitis associated with joint injury can promote synovial angiogenesis, which in turn accelerates inflammation and leads to synovial fibrosis (Zhang et al, 2021). At six weeks post-surgery, morphological signs of synovitis were prominent in knee joints that underwent surgery.…”

Section: Resultsmentioning

confidence: 99%

Gli1⁺ mesenchymal progenitors contribute to multilineage differentiation in a mouse model of post-traumatic joint injury

Magallanes

Liu

Zhang

et al. 2022

Preprint

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Complex injury and open reconstructive surgeries of the knee often lead to joint dysfunction that may alter the normal biomechanics of the joint. Two major complications that often arise are excessive deposition of fibrotic tissue and acquired heterotopic endochondral ossification. Knee arthrofibrosis is a fibrotic joint disorder where aberrant buildup of scar tissue and adhesions develop around the joint. Heterotopic ossification is ectopic bone formation around the periarticular tissues. Even though arthrofibrosis and heterotopic ossification pose an immense clinical problem, limited studies focus on their cellular and molecular mechanisms. Effective cell-targeted therapeutics are needed, but the cellular origin of both knee disorders remains elusive. Moreover, all the current animal models of knee arthrofibrosis and stiffness are developed in rats and rabbits, limiting genetic experiments that would allow us to explore the contribution of specific cellular targets to these knee pathologies. Here, we present a novel mouse model of post-traumatic joint injury where surgically induced injury and hyperextension of the knee lead to excessive deposition of disorganized collagen in the meniscus, synovium, and joint capsule in addition to formation of extra-skeletal bone in muscle and soft tissues within the joint capsule. As a functional outcome, arthrofibrosis and heterotopic endochondral ossification coupled with a significant increase in total joint stiffness were observed. By employing this model and genetic lineage tracing, we also demonstrate that Gli1+ mesenchymal progenitors proliferate after joint injury and contribute to fibrotic cells in the synovium and ectopic osteoblasts within the joint capsule. These findings demonstrate that Gli1+ cells are a major cellular contributor to knee arthrofibrosis and heterotopic ossification that manifests after knee injury. Our data collectively shows that genetic manipulation of Gli1+ cells in mice may offer a platform for identification of novel therapeutic targets to prevent chronic knee joint dysfunction after chronic injury.

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Synovial Fibrosis Involvement in Osteoarthritis

Cited by 42 publications

References 88 publications

Differential Metabotypes in Synovial Fibroblasts and Synovial Fluid in Hip Osteoarthritis Patients Support Inflammatory Responses

Differential Metabotypes in Synovial Fibroblasts and Synovial Fluid in Hip Osteoarthritis Patients Support Inflammatory Responses

Carnosine Alleviates Knee Osteoarthritis and Promotes Synoviocyte Protection via Activating the Nrf2/HO-1 Signaling Pathway: An In-Vivo and In-Vitro Study

Gli1⁺ mesenchymal progenitors contribute to multilineage differentiation in a mouse model of post-traumatic joint injury

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Synovial Fibrosis Involvement in Osteoarthritis

Cited by 42 publications

References 88 publications

Differential Metabotypes in Synovial Fibroblasts and Synovial Fluid in Hip Osteoarthritis Patients Support Inflammatory Responses

Differential Metabotypes in Synovial Fibroblasts and Synovial Fluid in Hip Osteoarthritis Patients Support Inflammatory Responses

Carnosine Alleviates Knee Osteoarthritis and Promotes Synoviocyte Protection via Activating the Nrf2/HO-1 Signaling Pathway: An In-Vivo and In-Vitro Study

Gli1+ mesenchymal progenitors contribute to multilineage differentiation in a mouse model of post-traumatic joint injury

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Gli1⁺ mesenchymal progenitors contribute to multilineage differentiation in a mouse model of post-traumatic joint injury