Loss of MMP-2 disrupts skeletal and craniofacial development and results in decreased bone mineralization, joint erosion and defects in osteoblast and osteoclast growth

The ‘vanishing bone’ or inherited osteolysis/arthritis syndromes represent a heterogeneous group of skeletal disorders characterized by mineralization defects of affected bones and joints. Differing in anatomical distribution, severity and associated syndromic features, gene identification in each ‘...

Full description

Saved in:

Bibliographic Details
Published in:	Human molecular genetics Vol. 16; no. 9; pp. 1113 - 1123
Main Authors:	Mosig, Rebecca A., Dowling, Oonagh, DiFeo, Analisa, Ramirez, Maria Celeste M., Parker, Ian C., Abe, Etsuko, Diouri, Janane, Aqeel, Aida Al, Wylie, James D., Oblander, Samantha A., Madri, Joseph, Bianco, Paolo, Apte, Suneel S., Zaidi, Mone, Doty, Stephen B., Majeska, Robert J., Schaffler, Mitchell B., Martignetti, John A.
Format:	Journal Article
Language:	English
Published:	Oxford Oxford University Press 01-05-2007 Oxford Publishing Limited (England)
Subjects:	Animals Arthritis - genetics Arthritis - metabolism Arthritis - pathology Biological and medical sciences Bone and Bones - abnormalities Bone and Bones - metabolism Bone and Bones - physiopathology Bone Remodeling - genetics Bone Remodeling - physiology Calcification, Physiologic - genetics Calcification, Physiologic - physiology Cell Proliferation - drug effects Cells, Cultured Craniofacial Abnormalities - enzymology Craniofacial Abnormalities - genetics Craniofacial Abnormalities - physiopathology Fundamental and applied biological sciences. Psychology Gene Deletion Genetics of eukaryotes. Biological and molecular evolution Humans Immunohistochemistry Joints - metabolism Joints - pathology Matrix Metalloproteinase 2 - genetics Matrix Metalloproteinase 2 - metabolism Mice Mice, Knockout Molecular and cellular biology Osteoblasts - enzymology Osteoblasts - metabolism Osteoblasts - pathology Osteoclasts - enzymology Osteoclasts - metabolism Osteoclasts - pathology Reverse Transcriptase Polymerase Chain Reaction RNA, Small Interfering - genetics Time Factors Tomography, X-Ray Computed Enzyme Growth Metalloendopeptidases Osteoclast Joint Gelatinase A Osteoarticular system Peptidases Mineralization Development Osteoblast Hydrolases Genetics Craniofacial Bone
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	The ‘vanishing bone’ or inherited osteolysis/arthritis syndromes represent a heterogeneous group of skeletal disorders characterized by mineralization defects of affected bones and joints. Differing in anatomical distribution, severity and associated syndromic features, gene identification in each ‘vanishing bone’ disorder should provide unique insights into genetic/molecular pathways contributing to the overall control of skeletal growth and development. We previously described and then demonstrated that the novel autosomal recessive osteolysis/arthritis syndrome, multicentric osteolysis with arthritis (MOA) (MIM #605156), was caused by inactivating mutations in the MMP2 gene [Al Aqeel, A., Al Sewairi, W., Edress, B., Gorlin, R.J., Desnick, R.J. and Martignetti, J.A. (2000) Inherited multicentric osteolysis with arthritis: A variant resembling Torg syndrome in a Saudi family. Am. J. Med. Genet., 93, 11–18.]. These in vivo results were counterintuitive and unexpected since previous in vitro studies suggested that MMP-2 overexpression and increased activity, not deficiency, would result in the bone and joint features of MOA. The apparent lack of a murine model [Itoh, T., Ikeda, T., Gomi, H., Nakao, S., Suzuki, T. and Itohara, S. (1997) Unaltered secretion of beta-amyloid precursor protein in gelatinase A (matrix metalloproteinase 2)-deficient mice. J. Biol. Chem., 272, 22389–22392.] has hindered studies on disease pathogenesis and, more fundamentally, in addressing the paradox of how functional loss of a single proteolytic enzyme results in an apparent increase in bone loss. Here, we report that Mmp2−/− mice display attenuated features of human MOA including progressive loss of bone mineral density, articular cartilage destruction and abnormal long bone and craniofacial development. Moreover, these changes are associated with markedly and developmentally restricted decreases in osteoblast and osteoclast numbers in vivo. Mmp2−/− mice have ∼50% fewer osteoblasts and osteoclasts than control littermates at 4 days of life but these differences have nearly resolved by 4 weeks of age. In addition, despite normal cell numbers in vivo at 8 weeks of life, Mmp2−/− bone marrow cells are unable to effectively support osteoblast and osteoclast growth and differentiation in culture. Targeted inhibition of MMP-2 using siRNA in human SaOS2 and murine MC3T3 osteoblast cell lines resulted in decreased cell proliferation rates. Taken together, our findings suggest that MMP-2 plays a direct role in early skeletal development and bone cell growth and proliferation. Thus, Mmp2−/− mice provide a valuable biological resource for studying the pathophysiological mechanisms underlying the human disease and defining the in vivo physiological role of MMP-2.
Bibliography:	ark:/67375/HXZ-D84K1HHL-2 istex:10E02C5DDF0C3D803470313A46F13E9F434B1A31 ArticleID:ddm060 Present address: Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH 44106, USA. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 author's current address: Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH 44106, USA.
ISSN:	0964-6906 1460-2083
DOI:	10.1093/hmg/ddm060