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Background  Lubricin/proteoglycan 4 (PRG4) is a mucinous glycoprotein secreted by synovial fibroblasts and superficial zone chondrocytes. Recently, we showed that recombinant human PRG4 (rhPRG4) is a putative ligand for CD44 receptor. rhPRG4-CD44 interaction inhibits cytokine-induced rheumatoid arthritis synoviocyte proliferation. The objective of this study is to decipher the autocrine function of PRG4 in regulating osteoarthritic synoviocyte proliferation and expression of catabolic and pro-inflammatory mediators under basal and interleukin-1 beta (IL-1β)-stimulated conditions.    Methods  Cytosolic and nuclear levels of nuclear factor kappa B (NFκB) p50 and p65 subunits in  Prg4    +/+   and  Prg4    -/-   synoviocytes were studied using western blot. Nuclear translocation of p50 and p65 proteins in osteoarthritis (OA) fibroblast-like synoviocytes (FLS) in response to IL-1β stimulation in the absence or presence of rhPRG4 was studied using DNA binding assays. OA synoviocyte (5000 cells per well) proliferation following IL-1β (20 ng/ml) treatment in the absence or presence of rhPRG4 (50–200 μg/ml) over 48 hours was determined using a colorimetric assay. Gene expression of matrix metalloproteinases ( MMPs ), tissue inhibitor of metallproteinases-1 ( TIMP-1 ),  TIMP-2 ,  IL-1 β,  IL-6 ,  IL-8 ,  TNF- α, cycloxygenae-2 ( COX2 ) and  PRG4  in unstimulated and IL-1β (1 ng/ml)-stimulated OA synoviocytes, in the presence or absence of rhPRG4 (100 and 200 μg/ml), was studied following incubation for 24 hours.    Results    Prg4    -/-   synoviocytes contained higher nuclear p50 and p65 levels compared to  Prg4    +/+   synoviocytes ( p  < 0.05). rhPRG4 (100 μg/ml) reduced p50 and p65 nuclear levels in  Prg4    +/+   and  Prg4   -/-  synoviocytes ( p  < 0.001). Similarly, rhPRG4 (200 μg/ml) inhibited NFκB translocation and cell proliferation in OA synoviocytes in a CD44-dependent manner ( p  < 0.001) via inhibition of IκBα phosphorylation. IL-1β reduced  PRG4  expression in OA synoviocytes and rhPRG4 (100 μg/ml) treatment reversed this effect ( p  < 0.001). rhPRG4 (200 μg/ml) reduced basal gene expression of  MMP-1 ,  MMP-3 ,  MMP-13 ,  IL-6 ,  IL-8 , and  PRG4  in OA synoviocytes, while increasing  TIMP-2  and cycloxygenase-2 ( COX2 ) expression ( p  < 0.001). rhPRG4 (200 μg/ml) reduced IL-1β induction of  MMP-1 ,  MMP-3 ,  MMP-9 ,  MMP-13 ,  IL-6 ,  IL-8 , and  COX2  expression in a CD44-dependent manner ( p  < 0.001).    Conclusion  PRG4 plays an important anti-inflammatory role in regulating OA synoviocyte proliferation and reduces basal and IL-1β-stimulated expression of catabolic mediators. Exogenous rhPRG4 autoregulates native PRG4 expression in OA synoviocytes.

The autocrine role of proteoglycan-4 (PRG4) in modulating osteoarthritic synoviocyte proliferation and expression of matrix degrading enzymes