Proteoglycan 4
PRG4 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Aliases | PRG4, CACP, HAPO, JCAP, MSF, SZP, bG174L6.2, proteoglycan 4 | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 604283; MGI: 1891344; HomoloGene: 130465; GeneCards: PRG4; OMA:PRG4 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Proteoglycan 4 or lubricin is a proteoglycan that in humans is encoded by the PRG4 gene.[5][6][7] It acts as a joint/boundary lubricant.[7]
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).[8][9] Due to the discovery that the 32-kDa amino terminal fragment of lubricin could stimulate in-vitro megakaryocyte growth, the gene responsible for the expression of lubricin was initially called "megakaryocyte-stimulating factor" (MSF).[10] However, 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.[11] The expression of lubricin has also been detected and the protein localized in tendon,[12] meniscus,[13] lung, liver, heart, bone,[14] ligament, muscle, and skin.[15] It is present in human plasma, where it binds to neutrophils via L-selectin.[16]
![](http://upload.wikimedia.org/wikipedia/commons/thumb/0/05/Lubricin_Lubricating_Function.png/331px-Lubricin_Lubricating_Function.png)
Lubricin shares many properties with other members of the mucin family and similarly plays important roles in protecting cartilage surface from protein deposition and cell adhesion, in inhibiting synovial cell overgrowth, and in preventing cartilage-cartilage adhesion.[17][18]
Early work on lubricin showed that it was able to lubricate non cartilaginous surfaces as effectively as whole synovial fluid, confirming its important biological lubrication role.[19] Understanding lubricin is key to understanding joint mechanics and friction-based diseases.[20]
Structure
The protein encoded by this gene is a approximately 345 kDa[21] 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[7] and more than 168 sites for O-linked glycosylation.[22]
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.[16][22] 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.[23] 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.[24][25] Lubricin's unglycosylated regions can interact with cartilage proteins.[26][27] This characteristic may aid in the molecule's boundary lubricating ability.
Lubricin is a close analog to vitronectin, as both of these proteins contain a somatomedin B-like (SMB) domain and a hemopexin-like chain. These domains play a unique role in cell-cell and cell-extracellular matrix interactions.[28] However, unlike vitronectin, lubricin carries a central mucin-like domain with a large number of repeating KEPAPTT motifs.[29]
In total, lubricin is approximately 200 nm +/- 50 nm in length and has a diameter of a few nanometers. The glycoprotein consists of >5% serine and >20% threonine residues, which give rise to a large number of O-glycosylations. These are thought to contain short polar (Galβ1-3GalNAcα1-Ser/Thr) and negatively charged (NeuAcα2-3Galβ1-3GalNAcα1α1-Ser/Thr) sugar groups. About two thirds of these sugar groups are capped with sialic acid, and the end domains of the glycoprotein are thought to be globular, due to the nature of their protein-like domains. The N-terminus of lubricin is associated with its SMB-like domains,[30] whereas the C-terminus is associated with the hemopexin-like domain.[31] Due to the protein's overall slight negative charge and the fact that the center of the protein carries negatively charged sugar groups, the two end domains are thought to carry much of the protein's positive charge.[18][23][32][22]
![Structure of lubricin](http://upload.wikimedia.org/wikipedia/commons/thumb/7/79/Structure_of_Lubricin.png/413px-Structure_of_Lubricin.png)
Lubricin's complex protein structure is termed "bottle brush," which refers to the large number of densely packed glycosylations on lubricin's backbone. Overall, lubricin's structure is similar to other mucin proteins and bottle brush polymers. This structure is key to its lubricating ability, which is ascribed to interchain repulsion. This leads to trapping of large quantities of solvent and the stabilization of a fluid-like cushioning layer, which enables bottle brush polymers to lower the friction between joints when external pressure is applied.[34][35]
Furthermore, lubricin's N-terminus is thought to create disulfide bonds between two lubricin monomers. The glycoprotein thus exists as both a monomer and a dimer.[30] The adsorption of lubricin to cartilage surfaces occurs through interactions on its N- and C- terminus, where its bottle brush structure plays a role in both coating and repelling similarly coated cartilage surfaces due to steric repulsion.[36][37][26] Lubricin's high degree of hydration is also thought to be involved in repulsion forces generated by lubricin between opposing cartilage surfaces.[38]
Shear studies of lubricin adsorbed between various hydrophilic and hydrophobic surfaces have confirmed the importance of the glycoprotein in boundary lubrication and wear protection in articular joints.[18] Lubricin's bottle brush structure is common among a number of human lubricating glycoproteins, and a number of studies have been conducted to mimic this.[39] Researchers have successfully designed low-friction polymers imitating lubricin's bottle-brush-like structure, further supporting the notion that it is lubricin's architecture which plays an important role in reducing friction.[40] Similarly, another study on zwitterionic polymer brushes, which intended to mimic the structure of bottle-brush polymers present in cartilage, found that the brushes produced super low fouling surfaces and super low friction surfaces.[41]
Clinical significance
Lubricin, as MSF, was detected in the urine of patients undergoing bone marrow transplantation during a period of acute thrombocytopenia.[42] Depletion of lubricin function has also been associated with camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP), an arthritis-like autosomal recessive disorder.[5]
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.[7]
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.[43] 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 lubricating effect for joints and tissues prone to wear and tear degradation.[44]
Furthermore, the synovial fluid of patients with rheumatoid arthritis and osteoarthritis has been shown to exhibit reduced levels of lubricin when compared to healthy patients.[45] Researchers are currently exploring potential applications of lubricin for treating these and other related diseases.[46] Thus far, adding supplement lubricin has been shown to restore the lubricating ability of synovial fluid from patients with established osteoarthritis.[47] Lubricin has been shown to also play a role in anti-inflammation for osteoarthritis patients. Additionally, reduced lubricin levels have also been observed in the synovial fluid of patients with ACL injuries, and decreased lubricating ability has been found in patients with traumatic synovitis.[48][49]
Lubricin, which is naturally present in human cornea-eyelid interface, has also been shown to play a key role in reducing friction between the cornea and conjunctiva of the eye.[50] Clinical trials of the use of recombinant lubricin eye drops for treatment of dry eye disease have thus far been relatively successful.[51]
References
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{{cite journal}}
: CS1 maint: DOI inactive as of April 2024 (link) - ^ Ludwig TE, McAllister JR, Lun V, Wiley JP, Schmidt TA (December 2012). "Diminished cartilage-lubricating ability of human osteoarthritic synovial fluid deficient in proteoglycan 4: Restoration through proteoglycan 4 supplementation". Arthritis and Rheumatism. 64 (12): 3963–71. doi:10.1002/art.34674. PMID 22933061.
- ^ Elsaid KA, Fleming BC, Oksendahl HL, Machan JT, Fadale PD, Hulstyn MJ, et al. (June 2008). "Decreased lubricin concentrations and markers of joint inflammation in the synovial fluid of patients with anterior cruciate ligament injury". Arthritis and Rheumatism. 58 (6): 1707–15. doi:10.1002/art.23495. PMC 2789974. PMID 18512776.
- ^ Jay GD, Zack J, Cha C (September 2001). "PA41 Traumatized knee joint synovial fluid fails to provide boundary lubrication among emergency department patients". Osteoarthritis and Cartilage. 9: S32. doi:10.1016/s1063-4584(01)80293-4.
- ^ Schmidt TA, Sullivan DA, Knop E, Richards SM, Knop N, Liu S, et al. (June 2013). "Transcription, translation, and function of lubricin, a boundary lubricant, at the ocular surface". JAMA Ophthalmology. 131 (6): 766–76. doi:10.1001/jamaophthalmol.2013.2385. PMC 3887468. PMID 23599181.
- ^ Lambiase A, Sullivan BD, Schmidt TA, Sullivan DA, Jay GD, Truitt ER, et al. (January 2017). "A Two-Week, Randomized, Double-masked Study to Evaluate Safety and Efficacy of Lubricin (150 μg/mL) Eye Drops Versus Sodium Hyaluronate (HA) 0.18% Eye Drops (Vismed®) in Patients with Moderate Dry Eye Disease". The Ocular Surface. 15 (1): 77–87. doi:10.1016/j.jtos.2016.08.004. PMID 27614318.
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, et al. (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. S2CID 22232515.
- Liu YJ, Lu SH, Xu B, Yang RC, Ren Q, Liu B, et al. (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. S2CID 2103324.
- Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, et al. (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. Bibcode:2004PNAS..10112130B. 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, et al. (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. S2CID 21403617.
- 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. S2CID 6804891.
- 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. Bibcode:2007PNAS..104.6194J. 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.
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- Volitinib
- Antibodies: Emibetuzumab
- Ficlatuzumab
- Flanvotumab
- Onartuzumab
- Rilotumumab
- Telisotuzumab
- Telisotuzumab vedotin
IGF-1 |
|
---|---|
IGF-2 |
|
Others |
- Antagonists: ALE-0540
- Dexamethasone
- EVT-901 (SAR-127963)
- Testosterone
- Antibodies: Against NGF: ABT-110 (PG110)
- ASP-6294
- Fasinumab
- Frunevetmab
- Fulranumab
- MEDI-578
- Ranevetmab
- Tanezumab
- Aptamers: Against NGF: RBM-004
- Decoy receptors: LEVI-04 (p75NTR-Fc)
- Agonists: Becaplermin
- Platelet-derived growth factor (A, B, C, D)
- Kinase inhibitors: Agerafenib
- Avapritinib
- Axitinib
- Crenolanib
- Imatinib
- Lenvatinib
- Masitinib
- Motesanib
- Nintedanib
- Pazopanib
- Radotinib
- Quizartinib
- Ripretinib
- Sunitinib
- Sorafenib
- Toceranib
- Antibodies: Olaratumab
- Ramucirumab
- Tovetumab
GFRα1 |
|
---|---|
GFRα2 |
|
GFRα3 |
|
GFRα4 |
|
Unsorted |
|
- See here instead.
TrkA |
|
---|---|
TrkB |
|
TrkC |
|
- Agonists: Placental growth factor (PGF)
- Ripretinib
- Telbermin
- VEGF (A, B, C, D (FIGF))
- Allosteric modulators: Cyclotraxin B
- Kinase inhibitors: Agerafenib
- Altiratinib
- Axitinib
- Cabozantinib
- Cediranib
- Fruquintinib
- Lapatinib
- Lenvatinib
- Motesanib
- Nintedanib
- Pazopanib
- Pegaptanib
- Rebastinib
- Regorafenib
- Semaxanib
- Sorafenib
- Sunitinib
- Toceranib
- Tivozanib
- Vandetanib
- WHI-P 154
- Antibodies: Alacizumab pegol
- Bevacizumab
- Icrucumab
- Ramucirumab
- Ranibizumab
- Decoy receptors: Aflibercept
- Additional growth factors: Adrenomedullin
- Colony-stimulating factors (see here instead)
- Connective tissue growth factor (CTGF)
- Ephrins (A1, A2, A3, A4, A5, B1, B2, B3)
- Erythropoietin (see here instead)
- Glucose-6-phosphate isomerase (GPI; PGI, PHI, AMF)
- Glia maturation factor (GMF)
- Hepatoma-derived growth factor (HDGF)
- Interleukins/T-cell growth factors (see here instead)
- Leukemia inhibitory factor (LIF)
- Macrophage-stimulating protein (MSP; HLP, HGFLP)
- Midkine (NEGF2)
- Migration-stimulating factor (MSF; PRG4)
- Oncomodulin
- Pituitary adenylate cyclase-activating peptide (PACAP)
- Pleiotrophin
- Renalase
- Thrombopoietin (see here instead)
- Wnt signaling proteins
- Additional growth factor receptor modulators: Cerebrolysin (neurotrophin mixture)