Crosstalk between CD4 T cells and synovial fibroblasts from human arthritic joints promotes hyaluronan-dependent leukocyte adhesion and inflammatory cytokine expression in vitro

Kang, Inkyung; Hundhausen, Christian; Evanko, Stephen P.; Malapati, Prasanthi; Workman, Gail; Chan, Christina K.; Rims, Cliff; Firestein, Gary S.; Boyle, David L.; MacDonald, Kevin M.; Buckner, Jane H.; Wight, Thomas N.

doi:10.1016/j.mbplus.2022.100110

Cited by 5 publications

(3 citation statements)

References 103 publications

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“…A KOA mouse model of destabilization of the medial meniscus [ 14 ] can be generated in house for that purpose to understand the efficacy and half-life of local MXD administration on pannus formation under a representative milieu of fibrogenic factors released by inflammatory leukocytes, which may not be fully replicated in culture [ 42 ]. However, the use of established co-culture models of osteoarthritis such as those integrating FSCs with effector T-cells, polarized macrophages, or defective osteochondral explants [ 16 , 20 , 49 ] could also provide a better understanding of the effects of MXD and novel anti-fibrotics by closely simulating the inflammatory microenvironment in vivo.…”

Section: Discussionmentioning

confidence: 99%

Minoxidil weakens newly synthesized collagen in fibrotic synoviocytes from osteoarthritis patients

Sarkovich,

Issa,

Longanecker

et al. 2023

J. exp. orthop.

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Purpose Synovial fibrosis (SFb) formation and turnover attributable to knee osteoarthritis (KOA) can impart painful stiffness and persist following arthroplasty. To supplement joint conditioning aimed at maximizing peri-operative function, we evaluated the antifibrotic effect of Minoxidil (MXD) on formation of pyridinoline (Pyd) cross-links catalyzed by Plod2-encoded lysyl hydroxylase (LH)2b that strengthen newly synthesized type-I collagen (COL1) in fibroblastic synovial cells (FSCs) from KOA patients. MXD was predicted to decrease Pyd without significant alterations to Col1a1 transcription by FSCs stimulated with transforming growth factor (TGF)β1. Methods Synovium from 10 KOA patients grouped by SFb severity was preserved for picrosirius and LH2b histology or culture. Protein and RNA were purified from fibrotic FSCs after 8 days with or without 0.5 µM MXD and/or 4 ng/mL of TGFβ1. COL1 and Pyd protein concentrations from ELISA and expression of Col1a1, Acta2, and Plod2 genes by qPCR were compared by parametric tests with α = 0.05. Results Histological LH2b expression corresponded to SFb severity. MXD attenuated COL1 output in KOA FSCs but only in the absence of TGFβ1 and consistently decreased Pyd under all conditions with significant downregulation of Plod2 but minimal alterations to Col1a1 and Acta2 transcripts. Conclusions MXD is an attractive candidate for local antifibrotic pharmacotherapy for SFb by compromising the integrity of newly formed fibrous deposits by FSCs during KOA and following arthroplasty. Targeted antifibrotic supplementation could improve physical therapy and arthroscopic lysis strategies aimed at breaking down joint scarring. However, the effect of MXD on other joint-specific TGFβ1-mediated processes or non-fibrotic components requires further investigation.

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Section: Discussionmentioning

confidence: 99%

Minoxidil weakens newly synthesized collagen in fibrotic synoviocytes from osteoarthritis patients

Sarkovich,

Issa,

Longanecker

et al. 2023

J. exp. orthop.

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“…The extracellular structural domain of FAP includes an eight-bladed b-propeller domain, which is thought to provide an abundant T cell epitope (67) to participate in T cell-mediated cellular immune processes. FLSs are also used as an immunosurveillance regulator in cancer and show a rich immune cross-linking effect with T cells, for instance, when CD4 + T cells are co-cultured with FLSs, which promotes the adhesion of monocytes (68). Meanwhile, RA-FLSs can bind to T cell receptors to stimulate T cell differentiation and act as an antigen-presenting cells for T cells (69), extracting and presenting autoantigens and human type II collagen to antigenspecific T cells.…”

Section: Immune Responsementioning

confidence: 99%

“…As mentioned earlier, the citrullinated proteins play an important part in RA, and related citrullinated autoantigens have been shown to promote the secretion of inflammatory factors in FLSs (112). In addition, the co-culture of FLSs with their recruited T cells produced a hyaluronic acid-rich synovial microenvironment in the ECM, which also significantly enhanced the expression of inflammatory cytokines, including IL-1, IL-6, IL-8, and TNF-a (68). FAP is expressed by FLSs in response to pathological conditions in the RA synovium, which is widely believed to act as a key regulator in the pathological microenvironment (113).…”

Section: Immune Responsementioning

confidence: 99%

Role and mechanism of fibroblast-activated protein-α expression on the surface of fibroblast-like synoviocytes in rheumatoid arthritis

Wang

Lan

et al. 2023

Front. Immunol.

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Fibroblast-activated protein-α (FAP) is a type II integrated serine protease expressed by activated fibroblasts during fibrosis or inflammation. Fibroblast-like synoviocytes (FLSs) in rheumatoid arthritis (RA) synovial sites abundantly and stably overexpress FAP and play important roles in regulating the cellular immune, inflammatory, invasion, migration, proliferation, and angiogenesis responses in the synovial region. Overexpression of FAP is regulated by the initial inflammatory microenvironment of the disease and epigenetic signaling, which promotes RA development by regulating FLSs or affecting the signaling cross-linking FLSs with other cells at the local synovium and inflammatory stimulation. At present, several treatment options targeting FAP are in the process of development. This review discusses the basic features of FAP expressed on the surface of FLSs and its role in RA pathophysiology and advances in targeted therapies.

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Causal associations between circulating immune cells and osteoarthritis: A bidirectional mendelian randomization study

Xu,

Wang,

Chen

et al. 2024

International Immunopharmacology

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Crosstalk between CD4 T cells and synovial fibroblasts from human arthritic joints promotes hyaluronan-dependent leukocyte adhesion and inflammatory cytokine expression in vitro

Cited by 5 publications

References 103 publications

Minoxidil weakens newly synthesized collagen in fibrotic synoviocytes from osteoarthritis patients

Minoxidil weakens newly synthesized collagen in fibrotic synoviocytes from osteoarthritis patients

Role and mechanism of fibroblast-activated protein-α expression on the surface of fibroblast-like synoviocytes in rheumatoid arthritis

Causal associations between circulating immune cells and osteoarthritis: A bidirectional mendelian randomization study

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