Tuysuz, B., Mosig, R., Altun, G., Sancak, S. & Glucksman, M. J. & Martignetti J.A. A novel matrix metalloproteinase 2 (MMP2) terminal hemopexin domain mutation in a family with multicentric osteolysis with nodulosis and arthritis with cardiac defects. Eur J Hum Genet 17, 565-572

Department of Pediatrics, Division of Genetics,Istanbul University Cerrahpasa Faculty of Medicine, Istanbul, Turkey.
European journal of human genetics: EJHG (Impact Factor: 4.35). 12/2008; 17(5):565-72. DOI: 10.1038/ejhg.2008.204
Source: PubMed


Multicentric osteolysis with nodulosis and arthropathy (MONA, NAO (OMIM no. 605156)) is an autosomal recessive member of the 'vanishing bone' syndromes and is notable for the extent of carpal and tarsal osteolysis and interphalangeal joint erosions, facial dysmorphia, and the presence of fibrocollagenous nodules. This rare disorder has been described previously in Saudi Arabian and Indian families. We now report on the first Turkish family with MONA, further confirming the panethnic nature of this disease. Strikingly, and in addition to the previously noted skeletal and joint features, affected members of this family also had congenital heart defects. Molecular analysis identified a novel MMP2 inactivating mutation that deletes the terminal hemopexin domains and thus confirmed the diagnosis of MONA. On the basis of these findings, we suggest that cardiac defects may also represent a component of this syndrome and thus a physiologically relevant target of MMP-2 activity.

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    • "Presentation of the patients described by Temtamy et al (12) is similar to our patient except growth retardation and lack of endocrine involvement. Growth retardation similar to that in our patient was present in the family described by Tuysuz et al (8). The evidence is lacking to assign growth retardation to this particular mutation. "
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    ABSTRACT: Torg and Winchester syndromes and patients reported by Al-AqeelSawairi as well as nodulosis-arthropathy-osteolysis (NAO) patients, patients with multicentric NAO share autosomal recessive inheritance. The common presenting symptomatology includes progressive osteolysis chiefly affecting the carpal, tarsal and interphalangeal joints. Here, we report a patient with Torg syndrome. Torg syndrome is caused by homozygous or compound heterozygous mutations in the matrix metalloproteinase 2 (MMP2) gene. MMP2 codes for a gelatinase that cleaves type IV collagen, a major component of basement membrane. The clinical presentation of our patient included moderate osteolysis of the small joints of the hands and knees, hirsutism, nodulosis sparing the palms and soles, corneal opacities and mild facial dysmorphism without gum hypertrophy. Genetic analysis showed that the patient was homozygous for a novel base variant c538 G>A (p.D180N) in the MMP2 gene. Both parents were carriers of the same mutated variant. Our patient had some previously unreported endocrine manifestations such as premature thelarche and elevated follicle-stimulating hormone levels.
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    • "Matrix metalloproteinases in avian growth plate syndrome in humans and a mouse model (Martignetti et al., 2001; Mosig et al., 2007; Tuysuz et al., 2009). In avian species, MMP-2 has a unique pattern of expression (Simsa et al., 2007a), which may indicate a role in proliferative chondrocyte survival, function, or both (Hasky-Negev et al., 2008). "
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    ABSTRACT: Long bone development depends on endochondral bone formation, a complex process requiring exquisite balance between hypertrophic cartilage (HC) formation and its ossification. Dysregulation of this process may result in skeletal dysplasias and heterotopic ossification. Endochondral ossification requires the precise orchestration of HC vascularization, extracellular matrix remodeling, and the recruitment of osteoclasts and osteoblasts. Matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF) and osteoclasts have all been shown to regulate endochondral ossification, but how their function interrelates is not known. We have investigated the functional relationship among these regulators of endochondral ossification, demonstrating that they have complementary but non-overlapping functions. MMP-9, VEGF and osteoclast deficiency all cause impaired growth plate ossification resulting in the accumulation of HC. VEGF mRNA and protein expression are increased at the MMP-9-/- growth plate, and VEGF activity contributes to endochondral ossification since sequestration of VEGF by soluble receptors results in further inhibition of growth plate vascularization and ossification. However, VEGF bioavailability is still limited in MMP-9 deficiency, as exogenous VEGF is able to rescue the MMP-9-/- phenotype, demonstrating that MMP-9 may partially, but not fully, regulate VEGF bioavailability. The organization of the HC extracellular matrix at the MMP-9-/- growth plate is altered, supporting a role for MMP-9 in HC remodeling. Inhibition of VEGF impairs osteoclast recruitment, whereas MMP-9 deficiency leads to an accumulation of osteoclasts at the chondro-osseous junction. Growth plate ossification in osteoclast-deficient mice is impaired in the presence of normal MMP-9 expression, indicating that other osteoclastic functions are also necessary. Our data delineate the complementary interplay between MMP-9, VEGF and osteoclast function that is necessary for normal endochondral bone formation and provide a molecular framework for investigating the molecular defects contributing to disorders of endochondral bone formation.
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