Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome

Abstract

The inherited osteolyses or 'vanishing bone' syndromes are a group of rare disorders of unknown etiology characterized by destruction and resorption of affected bones. The multicentric osteolyses are notable for interphalangeal joint erosions that mimic severe juvenile rheumatoid arthritis (OMIMs 166300, 259600, 259610 and 277950). We recently described an autosomal recessive form of multicentric osteolysis with carpal and tarsal resorption, crippling arthritic changes, marked osteoporosis, palmar and plantar subcutaneous nodules and distinctive facies in a number of consanguineous Saudi Arabian families. We localized the disease gene to 16q12-21 by using members of these families for a genome-wide search for homozygous-by-descent microsatellite markers. Haplotype analysis narrowed the critical region to a 1.2-cM region that spans the gene encoding MMP-2 (gelatinase A, collagenase type IV; (ref. 3). We detected no MMP2 enzymatic activity in the serum or fibroblasts of affected family members. We identified two family-specific homoallelic MMP2 mutations: R101H and Y244X. The nonsense mutation effects a deletion of the substrate-binding and catalytic sites and the fibronectin type II-like and hemopexin/TIMP2 binding domains. Based on molecular modeling, the missense mutation disrupts hydrogen bond formation within the highly conserved prodomain adjacent to the catalytic zinc ion.

Collagen Binding Properties of the Membrane Type-1 Matrix Metalloproteinase (MT1-MMP) Hemopexin C Domain

“…Moreover, mice deficient in MT1-MMP developed severe aberrations in type I collagen-abundant tissues, such as bone and skin, and the mice exhibited arthritis and scleroderma (21,22). In humans, homoallelic loss-of-function mutations in the MMP2 gene result in excessive bone resorption and arthritis (23). This condition resembles the phenotype of the MT1-MMP knockout mouse, supporting the close functional connection of MMP2 and MT1-MMP in regulating pericellular collagen homeostasis in mice and humans.…”

Renal macrophage migration and crystal phagocytosis via inflammatory-related gene expression during kidney stone formation and elimination in mice: Detection by association analysis of stone-related gene expression and microstructural observation

“…(25) Mmp2 encodes matrix metalloproteinase 2 (MMP2), as does gelatinase A, and secreted zinc-dependent endopeptidases that cleave protein components of the extracellular matrix, such as collagens and fibronectin, and is involved in cell migration by eliminating the surrounding extracellular matrix and basement membrane barriers. The role of MMP2 in kidney stone formation has never been investigated; however, it has been reported that matrix metalloproteinase-mediated cartilage destruction by macrophages (26) and mutation of the Mmp2 gene caused multicentric osteolysis and arthritis syndrome (27) ; this information is expected to show some role of MMP2 in crystal removal by macrophages. Fn1 encodes fibronectin (FN), a high-molecular-weight extracellular matrix glycoprotein that bonds with integrins, CD44, collagens, fibrin, and heparan sulfate.…”

Matrix remodeling during endochondral ossification

“…By contrast, MMP2 (gelatinase A) is diffusely expressed in osteoblasts, bone marrow cells and periosteum. Surprisingly, humans in whom both MMP2 alleles are mutated display an osteolysis and arthritis syndrome typified by destruction and resorption of affected bones [35], similar to the phenotype of MT1-MMP −/− mice [8,9] described below. Although an abnormal bone phenotype has not been described in MMP2 −/− mice [36], studies using different strains of mice are required as severity of bone phenotypes might be strain dependent.…”