Researchers identify sulfatase-2 as key protein that drives rheumatoid arthritis damage

A recent study published in the journal Cellular & Molecular Immunology has elucidated the potential role of sulfatase-2 (Sulf-2) expression in TNF-α-induced synovial inflammation using primary human RA synovial fibroblasts (RASFs).

Salahuddin Ahmed and co-workers noted that Sulf-2 expression was found to be significantly high in serum and synovial tissues of patients with RA and samples obtained from hTNFtg mice.  The researchers conducted ingenuity pathway analysis of RNA sequencing data and identified Sulf-2 as a primary target in fibroblasts and macrophages in RA.  Further analysis using Western blot, ELISA, and qRT‒PCR analyses corroborated that Sulf-2 knockdown decreased the TNF-α-induced expression of ICAM1, VCAM1, CAD11, PDPN, CCL5, CX3CL1, CXCL10, and CXCL11. Signaling studies identified the protein kinase C-delta (PKCδ) and c-Jun N-terminal kinase (JNK) pathways as the key  mechanisms involved in the TNF-α-mediated induction of proteins related to cellular adhesion and invasion.  The researchers noted that in human RASFs, the TNF-α-induced phosphorylation of PKCδ and JNK Sulf-2 knockdown was suppressed by Sulf-2 knockdown with siRNA and inhibition by OKN-007, thereby inhibiting the nuclear translocation and DNA binding activity of the transcription factors AP-1 and NF-κBp65. Crosstalk in TNF-α signaling between Sulf-2 expression and TNF receptor 1 was suggested by the positive correlation in the  expression of these 2 proteins, and their binding noted in coimmunoprecipitation assays.

A previous study by Kim et al. investigated Sulf expression in inflammatory cells in the human RA synovium by immunofluorescence staining. The researchers noted the upregulation of Sulfs in macrophages in response to inflammation, and its role in the active regulation of the antigen presentation and phagocytic activities of macrophages.

Though sulfatase-2 have been extensively investigated for their roles in different cancer types, the present study is first of its kind that has investigated its role in inflammatory or autoimmune diseases such as rheumatoid arthritis. The study reveals a novel role of Sulf-2 in TNF-α signaling and the activation of RA synoviocytes, and sheds light on the molecular processes involved in inflammation progression noted in RA. It may also help in developing novel treatment interventions for RA, which currently have no definite cure.


Siegel RJ, Singh AK, Panipinto PM, et al. Extracellular sulfatase-2 is overexpressed in rheumatoid arthritis and mediates the TNF-α-induced inflammatory activation of synovial fibroblasts [published online ahead of print, 2022 Sep 7]. Cell Mol Immunol. 2022;10

Kim HJ, Kim HS, Hong YH. Sulfatase 1 and sulfatase 2 as novel regulators of macrophage antigen presentation and phagocytosis. Yeungnam Univ J Med. 2021 Oct;38(4):326-336