Cartilage Oligomeric Matrix Protein (COMP) is a noncollagenous secreted protein of the extracellular matrix (ECM). It is a member of the thrombospondin family of proteins. It can be also called thrombospondin-5 (TSP-5). The family consists of thrombospondins 1-5 and can be divided into two subgroups. Group A includes TSP-1 and -2, homotrimers, whereas group B contains TSP-3, -4 and -5, homopentamers. Those are multifunctional adhesive glycoproteins which are synthesized, secreted, and incorporated into the extracellular matrix of a variety of cells.
COMP can be mainly detected in ligaments, tendons, and near chondrocytes. Chondrocytes play an important role in bone formation (osteogenesis). In the bones of the spine, hips, and limbs, the process of osteogenesis starts with the formation of cartilage, which is then converted into bone. This process is called endochondral ossification. COMP protein is involved in this process thanks to its direct effects on chondrocytes. It plays a role in cell proliferation and apoptosis, as well as in the regulation of cell movement and attachment. Mutations in COMP can cause two different skeletal dysplasias. (Expression of cartilage oligomeric matrix protein COMP by embryonic and adult osteoblasts, 2000).
COMP gene is located on chromosome 19p13.1. It is formed by 19 exons and spans 8,541 bases (start 18,893,583 bp from pter to end 18,902,123) oriented at the minus strand.
It is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, chicken, zebrafish, fruit fly, and mosquito.
This gene has 4 transcripts (splice variants). Variant 1 (COMP-001) is the longer and main protein-coding transcript.
CHEMICAL STRUCTURE AND IMAGES
COMP gene encodes a protein of 757 amino acids and its molecular weight is 82,860 kDa. Elements required for chondrocyte-specific expression lie within 375 bp of the translational start site, while DNA enhancer elements are located between 1.0 to 1.7 kb.
Its functional domains are:
Severe alterations in the secondary structure result in misfolding and retention in the chondrocyte rough endoplasmic reticulum. The CTD is a beta-sandwich that is composed of 15 antiparallel beta-strands. Type III repeats are a contiguous series of calcium-binding sites that associate with the CTD at multiple points (The crystal structure of the signature domain of cartilage oligomeric matrix protein: implications for collagen, glycosaminoglycan, and integrin-binding, 2009). There is an exposed potential metal-ion-dependent adhesion site (MIDAS) on one edge of the beta-sandwich. This could serve as a binding site for collagens and other ligands. Disease-causing mutations in COMP disrupt calcium-binding, disulfide bond formation, intramolecular interactions, or sites for potential ligand binding. (The crystal structure of the signature domain of cartilage oligomeric matrix protein: implications for collagen, glycosaminoglycan, and integrin-binding, 2009).
Oligomerization results from the formation of a five-stranded coiled-coil and disulfides bonds. Binding to other ECM proteins such as collagen appears to depend on divalent cations. TSP type III repeats bind two calcium ions, whereas the TSP C-terminal domain binds three calcium ions. A compact conformation is due to the presence of calcium. The cell attachment motif enables the attachment to chondrocytes. It mediates the induction of survival proteins and antiapoptotic proteins. Comp interacts with ITGB3 integrin, ITGA5 integrin and fibronectin 1 (FN1). Binding to FN1 requires the presence of divalent cations (Ca2+, Mg2+ or Mn2+). The greatest amount of binding is seen in the presence of Mn2+. COMP interacts with matrillins, which are cartilage matrix proteins, such as MATN1, MATN3, MATN4 and aggrecan (ACAN). It can also bind heparin, heparan sulfate and chondroitin sulfate. It interacts with collagen I, II, IX, XII, XIV, this is though dependent on the presence of zinc ions. (Collagen XII and XIV, New Partners of Cartilage Oligomeric Matrix Protein in the Skin Extracellular Matrix Suprastructure, 2012).
Binding to a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS12) and ITGA7 integrin has also been reported.
Protein Aminoacids Percentage
SYNTHESIS AND TURNOVER
COMP expression in normal human tissues (normalized intensities) has been investigated. Levels of mRNA are high in adipocytes, muscles, and lungs.
Protein expression data from MOPED and PaxDb detect COMP in blood serum, blood plasma, platelets, and kidney urine. The lower expression can be detected in the heart and brain. Further studies suggest its main expression in muscle, bone, ligament, synovium, blood vessel, tendon, and cartilage. (Cartilage oligomeric matrix protein is involved in human limb development and in the pathogenesis of osteoarthritis.,2006).
Glycosylation occurs in positions 121 and 742. Twentythree different disulfide bonds have been predicted. (The crystal structure of the signature domain of cartilage oligomeric matrix protein: implications for collagen, glycosaminoglycan and integrin binding., 2009).
The function and roles of ADAMTS-7 in inflammatory diseases, 2015
1 COMP plays an important role in normal skeletal development. It may regulate the expression of other genes involved in chondrogenesis by acting as a transcription factor for these genes. It is present during development, in the earliest stages of limb maturation and it is later found in joints regions. Its main role is assuring the structural integrity of cartilage, interacting with other extracellular matrix proteins, such as collagens and fibronectin. It may also directly stimulate chondrocyte proliferation. COMP and granulin-epithelin precursor (GEP), an autocrine growth factor, act together leading chondrocyte cells to mitosis. COMP expression was shown to enhance chondrogenesis. This protein also interacts with cell surface integrin receptors. (The role of cartilage oligomeric matrix protein (COMP) in skeletal disease.,2008). Moreover, it plays a role in catalyzing the assembly of collagen, promoting the formation of well-defined fibrils.
2 COMP is a potent suppressor of apoptosis in both primary chondrocytes and transformed cells. It protects HeLa and 293 cells against death, either in the presence or absence of tumor necrosis factor-alpha and is able to block activation of caspase 3 effect appears to be mediated by the inhibitor of apoptosis protein (IAP), a family of anti-apoptotic proteins. Levels of IAP are significantly elevated in the COMP-expressing cells. Down-regulation of this protein levels by small interfering RNAs blocks the ability of COMP to enhance survival. Survivin is the first gene identified to be up-regulated transcriptionally by COMP. (Cartilage oligomeric matrix protein protects cells against death by elevating members of the IAP family of survival proteins.,2008).
3 COMP is essential for maintaining vascular smooth muscle cells (VSMCs) contractile and differentiated, under physiological and pathological stimuli. Data strongly suggest that COMP is a novel inhibitor of vascular calcification. (Cartilage oligomeric matrix protein inhibits vascular smooth muscle calcification by interacting with bone morphogenetic protein-2.,2011).
Mutant COMP fails to fold properly and is entrapped along with other ECM proteins within the rER of affected chondrocytes. This intracellular retention is toxic to the chondrocytes, which eventually die prematurely. These events which reduce the number of chondrocytes in the growth plate ultimately reduce linear growth leading to dwarfism. (The role of cartilage oligomeric matrix protein (COMP) in skeletal disease., 2008).
Sequencing of the entire COMP coding region or of selected exons can diagnose two different skeletal dysplasias: Multiple Epiphyseal Dysplasia (MED) and Pseudoachondroplasia (PSACH).
Multiple Epiphyseal Dysplasia caused by COMP mutation is an autosomal dominant skeletal disorder characterized by short stature and early-onset osteoarthrosis. It affects 1 in 10,000 individuals. Patients have small capital femoral epiphyses and hypoplastic, poorly formed acetabular roofs. Other main characteristics are brachydactyly, ligamentous laxity, scoliosis, joint dysplasia, stiffness, and pain.
Pseudoachondroplasia is an autosomal dominant osteochondrodysplasia characterized by disproportionate short stature, deformity of the lower limbs, brachydactyly, loose joints, and ligamentous laxity. It affects 1 in 20,000 individuals.
COMP degradation is both parts of normal and defective joint turnover. When cartilage is broken down by a disease process, matrix proteins, such as COMP, are released into the synovial fluid and are later found in circulation. COMP can be thus considered as a biomarker for several conditions. This role has firstly been investigated in animal models. (Analysis of cartilage oligomeric matrix protein (COMP) degradation and synthesis in equine joint disease,2005). Further studies have then demonstrated its potential in human medicine. (Cartilage Oligomeric Matrix Protein (COMP): A Biomarker of Arthritis., 2009).
COMP levels are significantly decreased in patients with COMP mutations. Measuring the level of circulating COMP may be an easier, more rapid, and cost-efficient method for diagnosing PSACH and MED. (Circulating COMP is decreased in pseudoachondroplasia and multiple epiphyseal dysplasia patients carrying COMP mutations.).
On the other hand, increased amounts of COMP protein are produced in patients with osteoarthritis, rheumatoid arthritis, and even scoliosis. Its level can be also used to evaluate drug efficacy. (Cartilage oligomeric matrix protein level in rheumatic diseases: potential use as a marker for measuring articular cartilage damage and/or the therapeutic efficacy of treatments., 2007).
Solid-phase ELISA COMP assay is available. It has been designed to measure human COMP protein in serum or heparin plasma. It is based on a quantitative sandwich enzyme immunoassay principle.
A novel drug based on calcium is being studied and may have effect also on COMP protein.
Mutation in COMP gene could have even saved your life during II World War. The Ovitz family was a family of Jewish Romanian actors and traveling musicians. "I was saved by the grace of the devil", always told Perla Ovitz. They were ready to be killed in a gas chamber in Auschwitz and would have died if dr. Mengele had not suddenly appeared claiming his "dwarf family" for his studies. They were the largest family of dwarfs ever recorded and were the largest family to enter Auschwitz and to survive intact, counting twelve people. Seven of them had pseudoachondroplasia.
Click to watch the video about the Ovitz family