The synovium is a mesenchymal tissue composed mainly of fibroblasts with a lining and sublining that surrounds the joints. In rheumatoid arthritis (RA), the synovial tissue undergoes marked hyperplasia, becomes inflamed and invasive and destroys the joint 1 , 2 . Recently, we and others found that a subset of fibroblasts located in the sublining undergoes major expansion in RA and is linked to disease activity 3 , 4 , 5 . However, the molecular mechanism by which these fibroblasts differentiate and expand in RA remains unknown. Here, we identified a critical role for NOTCH3 signaling in the differentiation of perivascular and sublining CD90( THY1 )+ fibroblasts. Using single cell RNA-sequencing and synovial tissue organoids, we found that NOTCH3 signaling drives both transcriptional and spatial gradients in fibroblasts emanating from vascular endothelial cells outward. In active RA, NOTCH3 and NOTCH target genes are markedly upregulated in synovial fibroblasts. Importantly, genetic deletion of Notch3 or monoclonal antibody-blockade of NOTCH3 signaling attenuates inflammation and prevents joint damage in inflammatory arthritis. Our results indicate that synovial fibroblasts exhibit positional identity regulated by endothelium-derived Notch signaling and that this stromal crosstalk pathway underlies inflammation and pathology in inflammatory arthritis.

Suppressor of cytokine signaling 3 (SOCS3) is a key regulator of cytokine signaling in macrophages and T cells. Although SOCS3 seems to contribute to the balance between the pro-inflammatory actions of IL-6 family of cytokines and anti-inflammatory signaling of IL-10 by negatively regulating gp130/Jak/Stat3 signal transduction, how and the molecular mechanisms whereby SOCS3 controls the downstream impact of TLR4 are largely unknown and current data are controversial. Furthermore, very little is known regarding SOCS3 function in cells other than myeloid cells and T cells. Our previous study demonstrates that SOCS3 is expressed in osteoblasts and functions as a critical inhibitor of LPS-induced IL-6 expression. However, the function of SOCS3 in osteoblasts remains largely unknown. In the current study, we report for the first time that LPS stimulation of osteoblasts induces the transcriptional activation of matrix metalloproteinase (MMP)-13, a central regulator of bone resorption. Importantly, we demonstrate that SOCS3 overexpression leads to a significant decrease of LPS-induced MMP-13 expression in both primary murine calvariae osteoblasts and a mouse osteoblast-like cell line, MC3T3-E1. Our findings implicate SOCS3 as an important regulatory mediator in bone inflammatory diseases by targeting MMP-13.

Suppressor of cytokine signaling 3 (SOCS3) is a potent regulator of cytokine signaling in macrophages and T cells. In recent studies, evidence has been provided for SOCS3 activation in all major bone cells including osteoclasts, chondrocytes, synoviocytes, and osteoblasts. The investigation of SOCS3 function in bone remodeling systems implicates SOCS3 as a key signaling molecule in bone cell-mediated inflammatory responses. Both pro- and anti-inflammatory functions of SOCS3 have been demonstrated in different types of bone cells. This review provides an overview of the important role of SOCS3 in inflammatory responses of various bone cells and in bone inflammatory disorders such as periodontal disease and arthritis. Understanding the roles of SOCS3 in inflammatory diseases of bone and joints such as arthritis, osteomyelitis, and periodontal diseases is critical to revealing insights into signaling pathways that can be manipulated in potential therapeutic approaches.

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