PRG4

Proteoglycan 4
Identifiers
Symbols	PRG4 ; CACP; HAPO; JCAP; MSF; SZP; bG174L6.2
External IDs	OMIM: 604283 HomoloGene: 130465 GeneCards: PRG4 Gene
Gene ontology Molecular function • scavenger receptor activity • polysaccharide binding Cellular component • extracellular region Biological process • immune response • cell proliferation Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Protein domains
Orthologs
Species	Human	Mouse
Entrez	10216	96875
Ensembl	ENSG00000116690	ENSMUSG00000006014
UniProt	Q92954	Q9JM99
RefSeq (mRNA)	NM_001127708	NM_001110146
RefSeq (protein)	NP_001121180	NP_001103616
Location (UCSC)	Chr 1: 186.27 – 186.28 Mb	Chr 1: 150.45 – 150.47 Mb
PubMed search

Proteoglycan 4 or lubricin is a proteoglycan that in humans is encoded by the PRG4 gene.^[1][2][3] This proteoglycan acts as a joint/boundary lubricant.^[3]

Function

Lubricin is present in synovial fluid and on the surface (superficial layer) of articular cartilage and therefore plays an important role in joint lubrication and synovial homeostasis. When first isolated, cartilage lubricin was called "superficial zone protein" (SZP).^[4][5] Lubricin, MSF, and SZP are now collectively known as Proteoglycan 4 (hence PRG4 for the gene nomenclature). The expression of lubricin has also been detected and the protein localized in tendon,^[6] meniscus,^[7] lung, liver, heart, bone,^[8] ligament, muscle, and skin.^[9]

Structure

The protein encoded by this gene is a proteoglycan of approximately 345 kDa^[10] specifically synthesized by chondrocytes located at the surface of articular cartilage, and also by some synovial lining cells. The cDNA encodes a protein of 1,404 amino acids (human A isoform) with a somatomedin B homology domain, heparin-binding domains, multiple mucin-like repeats, a hemopexin domain, and an aggregation domain. There are 3 consensus sequences for N-glycosylation and 1 chondroitin sulfate substitution site.^[3]

Lubricin is a large, water-soluble glycoprotein with a molecular weight of 206,000 Daltons and consists of approximately equal proportions of protein and oligosaccharides. Electron microscope measurements show that the lubricin molecule is a partially extended flexible rod and, in solution, occupies a smaller spatial domain than would be expected from structural predictions.^[11] This characteristic may aid in the molecule's boundary lubricating ability.

Clinical significance

Lubricin, as MSF, was detected in the urine of patients undergoing bone marrow transplantation during a period of acute thrombocytopenia.^[12] Depletion of lubricin function has also been associated with camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP), an arthritis-like autosomal recessive disorder.^[13]

The locus for autosomal recessive camptodactyly-arthropathy-coxa vara-pericarditis syndrome maps to chromosome 1q25-q31 where the PRG4 gene is located. Cell overgrowth may be primary to the pathogenesis of this protein.^[3]

Lubricin’s role in improving tendon gliding has also been studied. While adding lubricin alone fails to have an impact on the tendon gliding resistance, the addition of cd-gelatin plus lubricin significantly lowered the gliding resistance of the tendons. This research can aid in improving the gliding ability of tendon grafts done clinically.^[14]

References

1. Marcelino J, Carpten JD, Suwairi WM, Gutierrez OM, Schwartz S, Robbins C, Sood R, Makalowska I, Baxevanis A, Johnstone B, Laxer RM, Zemel L, Kim CA, Herd JK, Ihle J, Williams C, Johnson M, Raman V, Alonso LG, Brunoni D, Gerstein A, Papadopoulos N, Bahabri SA, Trent JM, Warman ML (Dec 1999). "CACP, encoding a secreted proteoglycan, is mutated in camptodactyly-arthropathy-coxa vara-pericarditis syndrome". Nat Genet 23 (3): 319–22. doi:10.1038/15496. PMID 10545950.
2. Flannery CR, Hughes CE, Schumacher BL, Tudor D, Aydelotte MB, Kuettner KE, Caterson B (Mar 1999). "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". Biochem Biophys Res Commun 254 (3): 535–41. doi:10.1006/bbrc.1998.0104. PMID 9920774.
3. "Entrez Gene: PRG4 proteoglycan 4".
4. Schumacher BL, Block JA, Schmid TM, Aydelotte MB, Kuettner KE. (1994). "A novel proteoglycan synthesized and secreted by chondrocytes of the superficial zone of articular cartilage.". Arch Biochem Biophys 311 (1): 144–52. doi:10.1006/abbi.1994.1219. PMID 8185311.
5. Jay GD, et al. (2000). "Lubricin is a product of megakaryocyte stimulating factor gene expression by human synovial fibroblasts.". J Rheumatol 27 (3): 594–600. PMID 10743795.
6. Rees; Davies, JR; Tudor, D; Flannery, CR; Hughes, CE; Dent, CM; Caterson, B; et al. (2002). "Immunolocalisation and expression of proteoglycan 4 (cartilage superficial zone proteoglycan) in tendon". Matrix Biol 21 (7): 593–602. doi:10.1016/S0945-053X(02)00056-2. PMID 12475643.
7. Schumacher BL, et al. (2005). "Proteoglycan 4 (PRG4) synthesis and immunolocalization in bovine meniscus.". J Orthop Res 23 (3): 562–568. doi:10.1016/j.orthres.2004.11.011. PMID 15885476..
8. Ikegawa S, et al. (2000). "Isolation, characterization and mapping of the mouse and human PRG4 (proteoglycan 4) genes.". Cytogenet Cell Genet 90 (3-4): 291–297. doi:10.1159/000056791. PMID 11124536.
9. Sun Y, et al. (2006). "Mapping lubricin in canine musculoskeletal tissues.". Connect Tissue Res 47 (4): 215–221. doi:10.1080/03008200600846754. PMID 16987753..
10. Su JL, Schumacher BL, Lindley KM, et al. (June 2001). "Detection of superficial zone protein in human and animal body fluids by cross-species monoclonal antibodies specific to superficial zone protein". Hybridoma 20 (3): 149–57. doi:10.1089/027245701750293475. PMID 11461663.
11. Swann DA, et al. (1981). "The molecular structure of lubricating glycoprotein-I, the boundary lubricant for articular cartilage.". J Biol Chem 256 (11): 5921–5925. PMID 7240180.
12. Merberg DM et al. (1993) Comparison of vitronectin and megakaryocyte stimulating factor. In Biology of Vitronectins and their Receptors. (Preissner et al., eds) pp45-52 (Elsevier Science, Amsterdam).
13. Marcelino J, et al. (1999). "CACP, encoding a secreted proteoglycan, is mutated in camptodactyly-arthropathy-coxa vara-pericarditis syndrome.". Nat Genet 23 (3): 319–322. doi:10.1038/15496. PMID 10545950..
14. Taguchi M, Jay GD, et al. (Jan 2008). "Lubricin Surface Modification Improves Extrasynovial Tendon Gliding in a Canine Model in Vitro". The Journal of Bone and Joint Surgery 90 (1): 129–135. doi:10.2106/JBJS.G.00045. PMID 18171967.

Further reading

• Schumacher BL, Block JA, Schmid TM, et al. (1994). "A novel proteoglycan synthesized and secreted by chondrocytes of the superficial zone of articular cartilage.". Arch. Biochem. Biophys. 311 (1): 144–52. doi:10.1006/abbi.1994.1219. PMID 8185311.
• Bahabri SA, Suwairi WM, Laxer RM, et al. (1998). "The camptodactyly-arthropathy-coxa vara-pericarditis syndrome: clinical features and genetic mapping to human chromosome 1.". Arthritis Rheum. 41 (4): 730–5. doi:10.1002/1529-0131(199804)41:4<730::AID-ART22>3.0.CO;2-Y. PMID 9550484.
• Jay GD, Britt DE, Cha CJ (2000). "Lubricin is a product of megakaryocyte stimulating factor gene expression by human synovial fibroblasts.". J. Rheumatol. 27 (3): 594–600. PMID 10743795.
• Ikegawa S, Sano M, Koshizuka Y, Nakamura Y (2001). "Isolation, characterization and mapping of the mouse and human PRG4 (proteoglycan 4) genes.". Cytogenet. Cell Genet. 90 (3-4): 291–7. doi:10.1159/000056791. PMID 11124536.
• Rees SG, Davies JR, Tudor D, et al. (2003). "Immunolocalisation and expression of proteoglycan 4 (cartilage superficial zone proteoglycan) in tendon.". Matrix Biol. 21 (7): 593–602. doi:10.1016/S0945-053X(02)00056-2. PMID 12475643.
• Morawietz L, Gehrke T, Frommelt L, et al. (2003). "Differential gene expression in the periprosthetic membrane: lubricin as a new possible pathogenetic factor in prosthesis loosening.". Virchows Arch. 443 (1): 57–66. doi:10.1007/s00428-003-0818-y. PMID 12783322.
• Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs.". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
• Liu YJ, Lu SH, Xu B, et al. (2004). "Hemangiopoietin, a novel human growth factor for the primitive cells of both hematopoietic and endothelial cell lineages.". Blood 103 (12): 4449–56. doi:10.1182/blood-2003-06-1825. PMID 14976050.
• Beausoleil SA, Jedrychowski M, Schwartz D, et al. (2004). "Large-scale characterization of HeLa cell nuclear phosphoproteins.". Proc. Natl. Acad. Sci. U.S.A. 101 (33): 12130–5. doi:10.1073/pnas.0404720101. PMC 514446. PMID 15302935.
• de Haan G (2006). "A novel growth factor encoded by an old gene.". Haematologica 90 (2): 152. PMID 15710563.
• Rhee DK, Marcelino J, Al-Mayouf S, et al. (2005). "Consequences of disease-causing mutations on lubricin protein synthesis, secretion, and post-translational processing.". J. Biol. Chem. 280 (35): 31325–32. doi:10.1074/jbc.M505401200. PMID 16000300.
• Liu T, Qian WJ, Gritsenko MA, et al. (2006). "Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry.". J. Proteome Res. 4 (6): 2070–80. doi:10.1021/pr0502065. PMC 1850943. PMID 16335952.
• Alazami AM, Al-Mayouf SM, Wyngaard CA, Meyer B (2006). "Novel PRG4 mutations underlie CACP in Saudi families.". Hum. Mutat. 27 (2): 213. doi:10.1002/humu.9399. PMID 16429407.
• Gregory SG, Barlow KF, McLay KE, et al. (2006). "The DNA sequence and biological annotation of human chromosome 1.". Nature 441 (7091): 315–21. doi:10.1038/nature04727. PMID 16710414.
• Zhang D, Johnson LJ, Hsu HP, Spector M (2007). "Cartilaginous deposits in subchondral bone in regions of exposed bone in osteoarthritis of the human knee: histomorphometric study of PRG4 distribution in osteoarthritic cartilage.". J. Orthop. Res. 25 (7): 873–83. doi:10.1002/jor.20344. PMID 17343281.
• Jay GD, Torres JR, Warman ML, et al. (2007). "The role of lubricin in the mechanical behavior of synovial fluid.". Proc. Natl. Acad. Sci. U.S.A. 104 (15): 6194–9. doi:10.1073/pnas.0608558104. PMC 1851076. PMID 17404241.

External links

• PRG4 human gene location in the UCSC Genome Browser.
• PRG4 human gene details in the UCSC Genome Browser.