Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage oligomeric matrix protein gene

Briggs, Michael D.; Hoffman, Susan M.G.; King, Lily; Olsen, Anne S.; Mohrenweiser, Harvey W.; Leroy, Jules; Mortier, Geert; Rimoin, David L.; Lachman, Ralph S.; Gaines, E.

doi:10.1038/ng0795-330

Cited by 472 publications

(343 citation statements)

References 28 publications

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“…In mature cartilage, COMP is a major non-collagenous matrix protein, primarily located intraterritorially and concentrated in the superficial layers (Lorenzo & Heinegård, unpublished). That COMP may have critical functions in cartilage is underlined by the fact that a mutation in the calcium-binding domain is phenotypically manifested as pseudochondroplasia and multiple epiphyseal dysplasia [22]. An interesting feature of COMP is its release from cartilage during the erosion of the tissue seen in severe arthritis.…”

Section: Introductionmentioning

confidence: 99%

Cartilage oligomeric matrix protein (COMP)-induced arthritis in rats

Carlsén

Hansson

Olsson

et al. 1998

Clinical and Experimental Immunology

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SUMMARYIn rheumatoid arthritis peripheral cartilaginous joints are inflamed and eroded. One driving factor may be an immune response towards proteins in the cartilage. Here it is shown that cartilage oligomeric matrix protein (COMP), expressed specifically in cartilage, is arthritogenic in the rat. Both native and denatured rat COMP induced severe arthritis in selected rat strains. The arthritis occurred only in peripheral joints which were attacked by an erosive inflammatory process similar to that seen in the human disease. The disease was self-limited and no permanent destruction of joints was seen macroscopically. Disease development appeared to be dependent on an immune response to autologous (rat) COMP and not on cross-reactivity to other cartilage rat collagens (types II, IX and XI). The disease and the immune response to COMP were genetically controlled by the MHC; the RT1 u and RT1 l haplotypes were more susceptible than the a, c, d, f and n haplotypes. Both LEW and E3 gene backgrounds were highly permissive for disease induction. These findings suggest that the induction of arthritis with rat COMP represents a unique pathogenesis which is controlled by different genes compared with collagen-induced arthritis or adjuvant-induced arthritis.

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Section: Introductionmentioning

confidence: 99%

Cartilage oligomeric matrix protein (COMP)-induced arthritis in rats

Carlsén

Hansson

Olsson

et al. 1998

Clinical and Experimental Immunology

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“…Monitoring of COMP levels in either joint fluid or serum can be used to assess the presence and progression of arthritis (8)(9)(10)(11)(12)(13). Mutations in the human COMP gene have been linked to the development of pseudoachondroplasia and multiple epiphyseal dysplasia, autosomal-dominant forms of short-limb dwarfism characterized by short stature, N facies, epiphyseal abnormalities, and early-onset osteoarthritis [(OA); refs [14][15][16][17][18][19][20].…”

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confidence: 99%

ADAMTS‐7: a metalloproteinase that directly binds to and degrades cartilage oligomeric matrix protein

Liu¹,

et al. 2006

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Degradative fragments of cartilage oligomeric matrix protein (COMP) have been observed in arthritic patients. The physiological enzyme(s) that degrade COMP, however, remain unknown. We performed a yeast two-hybrid screen (Y2H) to search for proteins that associate with COMP to identify an interaction partner that might degrade it. One screen using the epidermal growth factor (EGF) domain of COMP as bait led to the discovery of ADAMTS-7. Rat ADAMTS-7 is composed of 1595 amino acids, and this protein exhibits higher expression in the musculoskeletal tissues. COMP binds directly to ADAMTS-7 in vitro and in native articular cartilage. ADAMTS-7 selectively interacts with the EGF repeat domain but not with the other three functional domains of COMP, whereas the four C-terminal TSP motifs of ADAMTS-7 are required and sufficient for association with COMP. The recombinant catalytic domain and intact ADAMTS-7 are capable of digesting COMP in vitro. The enzymatic activity of ADAMTS-7 requires the presence of Zn 2+ and appropriate pH (7.5-9.5), and the concentration of ADAMTS-7 in cartilage and synovium of patients with rheumatoid arthritis is significantly increased as compared to normal cartilage and synovium. ADAMTS-7 is the first metalloproteinase found to bind directly to and degrade COMP.-Liu, C., Kong, W., Ilalov, K., Yu, S., Xu, K., Prazak, L., Fajardo, M., Sehgal, B., Di Cesare, P. E. ADAMTS-7: a metalloproteinase that directly binds to and degrades cartilage oligomeric matrix protein. The extracellular matrix (ECM) of cartilage consists of several types of collagens, proteoglycans, and other noncollagenous macromolecules, all of which interact to form a highly specialized connective tissue (1). Early extracellular cartilage matrix degeneration in arthritis is the result of the action of degradative enzymes. As the severity of arthritis progresses, the synthesis and secretion of matrix-degrading enzymes markedly increase (2). The control 1 These authors contributed equally to this work.

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“…Mutations in either COMP or matrilin 3 are associated with human diseases that affect skeletal development (15)(16)(17), but development proceeds normally in both COMP and matrilin 3 single-deficient mice, without any pronounced skeletal abnormalities (18,19). To elucidate the role of COMP and matrilin 3 in osteogenesis and to investigate putative compensatory roles of the two adaptor proteins, we generated mice deficient in both molecules.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in both matrilin 3 and COMP have been linked to multiple epiphyseal dysplasia in humans, the pathogenesis of which includes both intracellular and extracellular alterations (15)(16)(17). Despite the large number of studies on matrilins and COMP, their roles in the function, assembly, and remodeling of the cartilage extracellular matrix are not fully understood.…”

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confidence: 99%

Abnormal bone quality in cartilage oligomeric matrix protein and matrilin 3 double‐deficient mice caused by increased tissue inhibitor of metalloproteinases 3 deposition and delayed aggrecan degradation

Groma¹,

Xin²,

Grskovic³

et al. 2012

Arthritis & Rheumatism

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Objective. Cartilage oligomeric matrix protein (COMP) and matrilin 3 are extracellular matrix proteins that are abundant in cartilage. As adaptor molecules, both proteins bridge and stabilize macromolecular networks consisting of fibrillar collagens and proteoglycans. Mutations in the genes coding for COMP and matrilin 3 have been linked to human chondrodysplasias, while in mice, deficiency in COMP or matrilin 3 does not cause any pronounced skeletal abnormalities. Given the similar functions of COMP and matrilin 3 in the assembly and stabilization of the extracellular matrix, our aim was to determine whether these proteins could functionally compensate for each other.Methods. To assess this putative redundancy of COMP and matrilin 3, we generated COMP/matrilin 3 double-deficient mice and performed an in-depth analysis of their skeletal development.Results. At the newborn stage, the overall skeletal morphology of the double mutants was normal, but at 1 month of age, the long bones were shortened and the total body length reduced. Peripheral quantitative computed tomography revealed increased metaphyseal trabecular bone mineral density in the femora. Moreover, the degradation of aggrecan in the cartilage remnants in the metaphyseal trabecular bone was delayed, paralleled by increased deposition of tissue inhibitor of metalloproteinases 3 (TIMP-3). The structure and morphology of the growth plate were grossly normal, but in the center, focal closures were observed, a phenotype very similar to that described in matrix metalloproteinase 13 (MMP-13)-deficient mice.Conclusion. We propose that a lack of COMP and matrilin 3 leads to increased deposition of TIMP-3, which causes partial inactivation of MMPs, including MMP-13, a mechanism that would explain the similarities in phenotype between COMP/matrilin 3 doubledeficient and MMP-13-deficient mice.The 2 major components of the cartilage extracellular matrix are the fibrillar collagens and the large hyaluronan-binding proteoglycan aggrecan. A variety of different proteins, including cartilage oligomeric matrix protein (COMP) and matrilin 3, modulate the assembly and structure of the extracellular matrix, generating complex functional networks. Matrilins are noncollagenous oligomeric extracellular matrix proteins with similar domain structure and function. Matrilin 1 and matrilin 3 are found almost exclusively in cartilage, while matrilin 2 and matrilin 4 have a broader tissue distribution. Subunits of matrilins 1 and 4 mainly form homotrimers, whereas subunits of matrilins 2 and 3 are found in homotetramers (1,2). In addition, heterotrimers consisting of matrilin 1 and matrilin 3 subunits can form. Matrilins function as adaptor proteins in the extracellular matrix and connect collagen fibrils with each other and with aggrecan (2). Via their von Willebrand type A-like domain, matrilins interact with several other matrix components, including COMP (3),

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Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage oligomeric matrix protein gene

Cited by 472 publications

References 28 publications

Cartilage oligomeric matrix protein (COMP)-induced arthritis in rats

Cartilage oligomeric matrix protein (COMP)-induced arthritis in rats

ADAMTS‐7: a metalloproteinase that directly binds to and degrades cartilage oligomeric matrix protein

Abnormal bone quality in cartilage oligomeric matrix protein and matrilin 3 double‐deficient mice caused by increased tissue inhibitor of metalloproteinases 3 deposition and delayed aggrecan degradation

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