Disease relevance of PRG4

• We have studied the autosomal recessive disorder camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP; MIM 208250) to identify biological pathways that lead to synoviocyte hyperplasia, the principal pathological feature of this syndrome [1].
• METHODS: Lubricin was purified from pooled synovial fluid aliquots with normal lubricating activity obtained from patients with osteoarthritis [2].
• Modifications to the structure of SZP, coupled with inhibition of SZP synthesis during inflammation, may account for the attachment and invasion of pannus observed in inflammatory joint diseases [3].
• Migration-stimulating factor (MSF) is a 70-kDa motogenic protein previously reported to be expressed by fetal and cancer patient fibroblasts cultured in vitro and present in the serum of breast cancer patients [4].
• Furthermore, an association between MSF expression and invasive capacity is observed in various breast adenocarcinoma cell lines [5].

High impact information on PRG4

• The CACP protein, which has previously been identified as both 'megakaryocyte stimulating factor precursor' and 'superficial zone protein', contains domains that have homology to somatomedin B, heparin-binding proteins, mucins and haemopexins [1].
• In addition to expression in joint synovium and cartilage, CACP is expressed in non-skeletal tissues including liver and pericardium [1].
• The availability of MSF obtained from cancer patient fibroblasts provides a potential means with which to examine the complex cellular interactions contributing to this process as well as develop a screening regime for identifying individuals at elevated risk of developing cancer [6].
• Data are now presented indicating that MSF present in the conditioned medium of fetal and cancer patient fibroblasts is precipitated at 10% saturation ammonium sulfate and binds to heparin and cation-exchange resins [6].
• Purified MSF has an estimated molecular mass of 70 kDa; amino acid analysis reveals a relatively high level of proline (13.34 residues per 100) [6].

Biological context of PRG4

• Lubricin, also known as superficial zone protein or PRG4, has many distinct biological functions, including lubrication, antiadhesion, and as a regulator of cell growth [7].
• During monolayer culture, S cells retained their PRG4-secreting phenotype, whereas in alginate culture the percentage of cells secreting PRG4 decreased with time [8].
• A locus responsible for causing CACP syndrome is assigned to a 1.9-cM interval on human chromosome 1q25-31 by homozygosity mapping [9].
• A 100% match was observed for exons 6 though 9 of MSF [2].
• Lubricin is a product of megakaryocyte stimulating factor gene expression by human synovial fibroblasts [2].

Anatomical context of PRG4

• OBJECTIVE: To determine whether the synovial fluid (SF) constituents hyaluronan (HA), proteoglycan 4 (PRG4), and surface-active phospholipids (SAPL) contribute to boundary lubrication, either independently or additively, at an articular cartilage-cartilage interface [10].
• Structural modifications to SZP, together with a reduction in synthesis during tendon inflammation with injury and disease may account for the formation of tendon adhesions and contribute to the overall dysfunction of the tissue [11].
• CONCLUSION: Lubricin is secreted by synovial fibroblasts via expression of the MSF gene [2].
• Articular cartilage superficial zone protein (SZP) is homologous to megakaryocyte stimulating factor precursor and Is a multifunctional proteoglycan with potential growth-promoting, cytoprotective, and lubricating properties in cartilage metabolism [3].
• Articular cartilage provides a low-friction surface for joint articulation, with boundary lubrication facilitated by proteoglycan 4 (PRG4), which is secreted by chondrocytes of the superficial zone [8].

Associations of PRG4 with chemical compounds

• OBJECTIVE: The boundary lubricating ability of human synovial fluid has been attributed to lubricin, a mucinous glycoprotein [2].
• Lubricating ability of lubricin was assayed in a friction apparatus that oscillates natural latex against a ring of polished glass [2].
• Courses 1, 3, and 5 consisted of fluorouracil as a 120-hour infusion (5FU-I) with cisplatin (CACP) as an intravenous (IV) bolus [12].
• We have previously reported that this difference in behaviour results from the secretion by fetal fibroblasts of a 'migration stimulating factor' (MSF) which is not made by their normal adult counterparts, and that MSF appears to act by stimulating the synthesis of hyaluronic acid (HA) [13].
• The human knee lubricin had a similar carbohydrate composition to bovine knee lubricin except for the higher glucosamine content, and the amino acid composition differed slightly [14].
• TNFalpha levels showed a significant negative relationship with log2 lubricin levels [15].

Regulatory relationships of PRG4

• Conversely, treatment with transforming growth factor-beta (TGF-beta) significantly upregulates lubricin synthesis, secretion and cartilage boundary association [16].

Other interactions of PRG4

• Static and dynamic compression regulate cartilage metabolism of PRoteoGlycan 4 (PRG4) [17].
• Oncostatin M also appears to be capable of modulating lubricin metabolism, with the potential to induce lubricin synthesis by chondrocytes [16].
• MSF is 1404 amino acids in size with multiple functional domains similar to vitronectin [2].
• CONCLUSION: Elevated coefficients of friction in arthritic joints occur concurrently with enhanced proteolytic degradation by up-regulated cathepsin B and other proteases, as well as decreased lubricin synthesis by synovial fibroblasts and superficial zone chondrocytes [18].

Analytical, diagnostic and therapeutic context of PRG4

• Immunohistochemistry revealed that all compression protocols also affected the number of cells expressing PRG4 [17].
• RESULTS: Purified lubricin possesses an apparent molecular weight of 280 kDa on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) [2].
• Native and lubricin deglycosylated with O-glycosidase DS and NANase III were trypsinized and sequenced by liquid chromatography mass spectrometry [2].
• This study investigated lubricin in canine musculoskeletal tissues using RT-PCR and immunohistochemistry [7].
• In this study, msf is linked to prosthesis loosening for the first time [19].

References