Proteoglycan 4

PRG4
Identifiers
AliasesPRG4, CACP, HAPO, JCAP, MSF, SZP, bG174L6.2, proteoglycan 4
External IDsHomoloGene: 130465 GeneCards: PRG4
Gene location (Human)
Chr.Chromosome 1 (human)[1]
Band1q31.1Start186,296,279 bp[1]
End186,314,562 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

10216

n/a

Ensembl

ENSG00000116690

n/a

UniProt

Q92954

n/a

RefSeq (mRNA)

NM_005807
NM_001127708
NM_001127709
NM_001127710
NM_001303232

n/a

RefSeq (protein)

NP_001121180
NP_001121181
NP_001121182
NP_001290161
NP_005798

n/a

Location (UCSC)Chr 1: 186.3 – 186.31 Mbn/a
PubMed search[2]n/a
Wikidata
View/Edit Human

Proteoglycan 4 or lubricin is a proteoglycan that in humans is encoded by the PRG4 gene.[3][4][5] It acts as a joint/boundary lubricant.[5]

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)[6][7]. Lubricin, MSF, and SZP are now collectively known as Proteoglycan 4 (hence PRG4 for the gene nomenclature).The evidence that lubricin is actually a proteoglycan is not solid[8]. The expression of lubricin has also been detected and the protein localized in tendon,[9] meniscus,[10] lung, liver, heart, bone,[11] ligament, muscle, and skin.[12] It is present in human plasma, where it binds to neutrophils via L-selectin.[13]

Structure

The protein encoded by this gene is a approximately 345 kDa[14] specifically synthesized by chondrocytes located at the surface of articular cartilage, and also by 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[5] and more than 168 sites for O-linked glycosylation[15]

Lubricin is a large glycoprotein that consists of approximately equal proportions of protein and oligosaccharides. The oligosaccharides are O-linked both with and without sialic acid..[13][15] 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.[16] The large glycosylated region (i. e mucin domain) of lubricin makes it a water-soluble synovial fluid protein. In synovial fluid it interacts with Galectin-3 that improves its lubricating property.[17] Lubricins unglycosylated regions can interact cartilage proteins.[18][19] 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.[20] Depletion of lubricin function has also been associated with camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP), an arthritis-like autosomal recessive disorder.[3]

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.[5]

Lubricin’s role in improving tendon gliding has also been studied. While adding lubricin alone fails to affect 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.[21] Extracorporeal shockwave therapy application has been shown to induce an increased lubricin expression in tendons and septa of rat hindlimbs, which might suggest a beneficial lubricanting effect for joints and tissues prone to wear and tear degradation.[22]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000116690 - Ensembl, May 2017
  2. ↑ "Human PubMed Reference:".
  3. 1 2 Marcelino J, Carpten JD, Suwairi WM, Gutierrez OM, Schwartz S, Robbins C, et al. (November 1999). "CACP, encoding a secreted proteoglycan, is mutated in camptodactyly-arthropathy-coxa vara-pericarditis syndrome". Nature Genetics. 23 (3): 319–22. doi:10.1038/15496. PMID 10545950.
  4. ↑ Flannery CR, Hughes CE, Schumacher BL, Tudor D, Aydelotte MB, Kuettner KE, Caterson B (January 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". Biochemical and Biophysical Research Communications. 254 (3): 535–41. doi:10.1006/bbrc.1998.0104. PMID 9920774.
  5. 1 2 3 4 "Entrez Gene: PRG4 proteoglycan 4".
  6. ↑ Schumacher BL, Block JA, Schmid TM, Aydelotte MB, Kuettner KE (May 1994). "A novel proteoglycan synthesized and secreted by chondrocytes of the superficial zone of articular cartilage". Archives of Biochemistry and Biophysics. 311 (1): 144–52. doi:10.1006/abbi.1994.1219. PMID 8185311.
  7. ↑ Jay GD, Britt DE, Cha CJ (March 2000). "Lubricin is a product of megakaryocyte stimulating factor gene expression by human synovial fibroblasts". The Journal of Rheumatology. 27 (3): 594–600. PMID 10743795.
  8. ↑ Lord MS, Estrella RP, Chuang CY, Youssef P, Karlsson NG, Flannery CR, Whitelock JM (2012). "Not all lubricin isoforms are substituted with a glycosaminoglycan chain". Connective Tissue Research. 53 (2): 132–41. doi:10.3109/03008207.2011.614364. PMID 21966936.
  9. ↑ Rees SG, Davies JR, Tudor D, Flannery CR, Hughes CE, Dent CM, Caterson B (November 2002). "Immunolocalisation and expression of proteoglycan 4 (cartilage superficial zone proteoglycan) in tendon". Matrix Biology. 21 (7): 593–602. doi:10.1016/S0945-053X(02)00056-2. PMID 12475643.
  10. ↑ Schumacher BL, Schmidt TA, Voegtline MS, Chen AC, Sah RL (May 2005). "Proteoglycan 4 (PRG4) synthesis and immunolocalization in bovine meniscus". Journal of Orthopaedic Research. 23 (3): 562–8. doi:10.1016/j.orthres.2004.11.011. PMID 15885476. .
  11. ↑ Ikegawa S, Sano M, Koshizuka Y, Nakamura Y (2000). "Isolation, characterization and mapping of the mouse and human PRG4 (proteoglycan 4) genes". Cytogenetics and Cell Genetics. 90 (3–4): 291–7. doi:10.1159/000056791. PMID 11124536.
  12. ↑ Sun Y, Berger EJ, Zhao C, An KN, Amadio PC, Jay G (2006). "Mapping lubricin in canine musculoskeletal tissues". Connective Tissue Research. 47 (4): 215–21. doi:10.1080/03008200600846754. PMID 16987753. .
  13. 1 2 Jin C, Ekwall AK, Bylund J, Björkman L, Estrella RP, Whitelock JM, Eisler T, Bokarewa M, Karlsson NG (October 2012). "Human synovial lubricin expresses sialyl Lewis x determinant and has L-selectin ligand activity". The Journal of Biological Chemistry. 287 (43): 35922–33. doi:10.1074/jbc.M112.363119. PMC 3476260. PMID 22930755.
  14. ↑ Su JL, Schumacher BL, Lindley KM, Soloveychik V, Burkhart W, Triantafillou JA, Kuettner K, Schmid T (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.
  15. 1 2 Ali L, Flowers SA, Jin C, Bennet EP, Ekwall AK, Karlsson NG (December 2014). "The O-glycomap of lubricin, a novel mucin responsible for joint lubrication, identified by site-specific glycopeptide analysis". Molecular & Cellular Proteomics. 13 (12): 3396–409. doi:10.1074/mcp.M114.040865. PMC 4256492. PMID 25187573.
  16. ↑ Swann DA, Slayter HS, Silver FH (June 1981). "The molecular structure of lubricating glycoprotein-I, the boundary lubricant for articular cartilage". The Journal of Biological Chemistry. 256 (11): 5921–5. PMID 7240180.
  17. ↑ Reesink HL, Bonnevie ED, Liu S, Shurer CR, Hollander MJ, Bonassar LJ, Nixon AJ (2016). "Galectin-3 Binds to Lubricin and Reinforces the Lubricating Boundary Layer of Articular Cartilage". Scientific Reports. 6: 25463. doi:10.1038/srep25463. PMC 4860590. PMID 27157803.
  18. ↑ Flowers SA, Kalamajski S, Ali L, Björkman LI, Raj JR, Aspberg A, Karlsson NG, Jin C (September 2017). "Cartilage oligomeric matrix protein forms protein complexes with synovial lubricin via non-covalent and covalent interactions". Osteoarthritis and Cartilage. 25 (9): 1496–1504. doi:10.1016/j.joca.2017.03.016. PMID 28373131.
  19. ↑ Raj A, Wang M, Liu C, Ali L, Karlsson NG, Claesson PM, Dėdinaitė A (June 2017). "Molecular synergy in biolubrication: The role of cartilage oligomeric matrix protein (COMP) in surface-structuring of lubricin". Journal of Colloid and Interface Science. 495: 200–206. doi:10.1016/j.jcis.2017.02.007. PMID 28208081.
  20. ↑ 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).
  21. ↑ Taguchi M, Sun YL, Zhao C, Zobitz ME, Cha CJ, Jay GD, An KN, Amadio PC (January 2008). "Lubricin surface modification improves extrasynovial tendon gliding in a canine model in vitro". The Journal of Bone and Joint Surgery. American Volume. 90 (1): 129–35. doi:10.2106/JBJS.G.00045. PMID 18171967.
  22. ↑ Zhang D, Kearney CJ, Cheriyan T, Schmid TM, Spector M (November 2011). "Extracorporeal shockwave-induced expression of lubricin in tendons and septa". Cell and Tissue Research. 346 (2): 255–62. doi:10.1007/s00441-011-1258-7. PMID 22009294.

Further reading

  • Bahabri SA, Suwairi WM, Laxer RM, Polinkovsky A, Dalaan AA, Warman ML (April 1998). "The camptodactyly-arthropathy-coxa vara-pericarditis syndrome: clinical features and genetic mapping to human chromosome 1". Arthritis and Rheumatism. 41 (4): 730–5. doi:10.1002/1529-0131(199804)41:4<730::AID-ART22>3.0.CO;2-Y. PMID 9550484.
  • Morawietz L, Gehrke T, Frommelt L, Gratze P, Bosio A, Möller J, Gerstmayer B, Krenn V (July 2003). "Differential gene expression in the periprosthetic membrane: lubricin as a new possible pathogenetic factor in prosthesis loosening". Virchows Archiv. 443 (1): 57–66. doi:10.1007/s00428-003-0818-y. PMID 12783322.
  • Liu YJ, Lu SH, Xu B, Yang RC, Ren Q, Liu B, Li B, Lu M, Yan FY, Han ZB, Han ZC (June 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, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP (August 2004). "Large-scale characterization of HeLa cell nuclear phosphoproteins". Proceedings of the National Academy of Sciences of the United States of America. 101 (33): 12130–5. doi:10.1073/pnas.0404720101. PMC 514446. PMID 15302935.
  • de Haan G (February 2005). "A novel growth factor encoded by an old gene". Haematologica. 90 (2): 152. PMID 15710563.
  • Rhee DK, Marcelino J, Al-Mayouf S, Schelling DK, Bartels CF, Cui Y, Laxer R, Goldbach-Mansky R, Warman ML (September 2005). "Consequences of disease-causing mutations on lubricin protein synthesis, secretion, and post-translational processing". The Journal of Biological Chemistry. 280 (35): 31325–32. doi:10.1074/jbc.M505401200. PMID 16000300.
  • Liu T, Qian WJ, Gritsenko MA, Camp DG, Monroe ME, Moore RJ, Smith RD (2006). "Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry". Journal of Proteome Research. 4 (6): 2070–80. doi:10.1021/pr0502065. PMC 1850943. PMID 16335952.
  • Alazami AM, Al-Mayouf SM, Wyngaard CA, Meyer B (February 2006). "Novel PRG4 mutations underlie CACP in Saudi families". Human Mutation. 27 (2): 213. doi:10.1002/humu.9399. PMID 16429407.
  • Zhang D, Johnson LJ, Hsu HP, Spector M (July 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". Journal of Orthopaedic Research. 25 (7): 873–83. doi:10.1002/jor.20344. PMID 17343281.
  • Jay GD, Torres JR, Warman ML, Laderer MC, Breuer KS (April 2007). "The role of lubricin in the mechanical behavior of synovial fluid". Proceedings of the National Academy of Sciences of the United States of America. 104 (15): 6194–9. doi:10.1073/pnas.0608558104. PMC 1851076. PMID 17404241.
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