Proteoglycan 4

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). 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). 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. The expression of lubricin has also been detected and the protein localized in tendon, meniscus, lung, liver, heart, bone, ligament, muscle, and skin. It is present in human plasma, where it binds to neutrophils via L-selectin. 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. 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. Understanding lubricin is key to understanding joint mechanics and friction-based diseases. == Structure ==

The protein encoded by this gene is a approximately 345 kDa 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 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. 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. Lubricin's unglycosylated regions can interact with cartilage proteins. 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. However, unlike vitronectin, lubricin carries a central mucin-like domain with a large number of repeating KEPAPTT motifs. 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, whereas the C-terminus is associated with the hemopexin-like domain. 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. 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. 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. 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. 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. == Clinical significance ==

Lubricin, as MSF, was detected in the urine of patients undergoing bone marrow transplantation during a period of acute thrombocytopenia. Depletion of lubricin function has also been associated with camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP), an arthritis-like autosomal recessive disorder. 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. 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. Researchers are currently exploring potential applications of lubricin for treating these and other related diseases. Thus far, adding supplement lubricin has been shown to restore the lubricating ability of synovial fluid from patients with established osteoarthritis. 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. 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. Clinical trials of the use of recombinant lubricin eye drops for treatment of dry eye disease have thus far been relatively successful. == References ==