Human Adult Fibroblast‐like Synoviocytes and Articular Chondrocytes Exhibit Prominent Overlap in Their Transcriptomic Signatures

Jones, Kyle M.; Angelozzi, Marco; Gangishetti, Umesh; Haseeb, Abdul; Charleroy, Charles de; Lefebvre, Véronique; Bhattaram, Pallavi

doi:10.1002/acr2.11255

Cited by 2 publications

(1 citation statement)

References 37 publications

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“…Experiments on human SFs were performed according to the guidelines and approval of the Emory University Institutional Review Board. OA SFs were prepared from the knee synovium collected from OA patients undergoing total joint replacement as described in our previous publications [ 33 , 34 ]. RA SFs isolated from the knee synovium of RA patients were collected from cadaveric donors within 48 h of death and were purchased from Articular Engineering, LLC.…”

Section: Methodsmentioning

confidence: 99%

MyD88 dimerization inhibitor ST2825 targets the aggressiveness of synovial fibroblasts in rheumatoid arthritis patients

Ramirez-Perez,

Vekariya,

Gautam

et al. 2023

Arthritis Res Ther

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Background Dimerization of the myeloid differentiation primary response 88 protein (MyD88) plays a pivotal role in the exacerbated response to innate immunity-dependent signaling in rheumatoid arthritis (RA). ST2825 is a highly specific inhibitor of MyD88 dimerization, previously shown to inhibit the pro-inflammatory gene expression in peripheral blood mononuclear cells from RA patients (RA PBMC). In this study, we elucidated the effect of disrupting MyD88 dimerization by ST2825 on the pathological properties of synovial fibroblasts from RA patients (RA SFs). Methods RA SFs were treated with varying concentrations of ST2825 in the presence or absence of bacterial lipopolysaccharides (LPS) to activate innate immunity-dependent TLR signaling. The DNA content of the RA SFs was quantified by imaging cytometry to investigate the effect of ST2825 on different phases of the cell cycle and apoptosis. RNA-seq was used to assess the global response of the RA SF toward ST2825. The invasiveness of RA SFs in Matrigel matrices was measured in organoid cultures. SFs from osteoarthritis (OA SFs) patients and healthy dermal fibroblasts were used as controls. Results ST2825 reduced the proliferation of SFs by arresting the cells in the G0/G1 phase of the cell cycle. In support of this finding, transcriptomic analysis by RNA-seq showed that ST2825 may have induced cell cycle arrest by primarily inhibiting the expression of critical cell cycle regulators Cyclin E2 and members of the E2F family transcription factors. Concurrently, ST2825 also downregulated the genes encoding for pain, inflammation, and joint catabolism mediators while upregulating the genes required for the translocation of nuclear proteins into the mitochondria and members of the mitochondrial respiratory complex 1. Finally, we demonstrated that ST2825 inhibited the invasiveness of RA SFs, by showing decreased migration of LPS-treated RA SFs in spheroid cultures. Conclusions The pathological properties of the RA SFs, in terms of their aberrant proliferation, increased invasiveness, upregulation of pain and inflammation mediators, and disruption of mitochondrial homeostasis, were attenuated by ST2825 treatment. Taken together with the previously reported anti-inflammatory effects of ST2825 in RA PBMC, this study strongly suggests that targeting MyD88 dimerization could mitigate both systemic and synovial pathologies in a variety of inflammatory arthritic diseases.

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Section: Methodsmentioning

confidence: 99%

MyD88 dimerization inhibitor ST2825 targets the aggressiveness of synovial fibroblasts in rheumatoid arthritis patients

Ramirez-Perez,

Vekariya,

Gautam

et al. 2023

Arthritis Res Ther

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Osteoarthritis genetic risk acting on the galactosyltransferase gene COLGALT2 has opposing functional effects in articulating joint tissues

et al. 2023

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Background Investigation of cartilage and chondrocytes has revealed that the osteoarthritis risk marked by the independent DNA variants rs11583641 and rs1046934 mediate their effects by decreasing the methylation status of CpG dinucleotides in enhancers and increasing the expression of shared target gene COLGALT2. We set out to investigate if these functional effects operate in a non-cartilaginous joint tissue. Methods Nucleic acids were extracted from the synovium of osteoarthritis patients. Samples were genotyped, and DNA methylation was quantified by pyrosequencing at CpGs within the COLGALT2 enhancers. CpGs were tested for enhancer effects using a synovial cell line and a reporter gene assay. DNA methylation was altered using epigenetic editing, with the impact on gene expression determined using quantitative polymerase chain reaction. In silico analysis complemented laboratory experiments. Results The rs1046934 genotype did not associate with DNA methylation or COLGALT2 expression in the synovium, whereas the rs11583641 genotype did. Surprisingly, the effects for rs11583641 were opposite to those previously observed in cartilage. Epigenetic editing in synovial cells revealed that enhancer methylation is causally linked to COLGALT2 expression. Conclusions This is the first direct demonstration for osteoarthritis genetic risk of a functional link between DNA methylation and gene expression operating in opposite directions between articular joint tissues. It highlights pleiotropy in the action of osteoarthritis risk and provides a cautionary note in the application of future genetically based osteoarthritis therapies: an intervention that decreases the detrimental effect of a risk allele in one joint tissue may inadvertently increase its detrimental effect in another joint tissue.

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Human Adult Fibroblast‐like Synoviocytes and Articular Chondrocytes Exhibit Prominent Overlap in Their Transcriptomic Signatures

Cited by 2 publications

References 37 publications

MyD88 dimerization inhibitor ST2825 targets the aggressiveness of synovial fibroblasts in rheumatoid arthritis patients

MyD88 dimerization inhibitor ST2825 targets the aggressiveness of synovial fibroblasts in rheumatoid arthritis patients

Osteoarthritis genetic risk acting on the galactosyltransferase gene COLGALT2 has opposing functional effects in articulating joint tissues

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