Human Molecular Genetics Advance Access originally published online on March 30, 2007
Human Molecular Genetics 2007 16(9):1113-1123; doi:10.1093/hmg/ddm060
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Loss of MMP-2 disrupts skeletal and craniofacial development and results in decreased bone mineralization, joint erosion and defects in osteoblast and osteoclast growth
1 Department of Genetics and Genomic Sciences, 2 Mount Sinai Bone Program, 3 Department of Medicine, 4 Department of Orthopedics, 5 Department of Oncological Sciences, 6 Department of Pediatrics, Mount Sinai School of Medicine, New York, NY 10029, USA, 7 Mineralized Tissue Laboratory, Hospital for Special Surgery, New York, NY 10021, USA, 8 Riyadh Armed Forces Hospital, Riyadh, Kingdom of Saudi Arabia, 9 Department of Biomedical Engineering and Orthopedic Research Center, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA, 10 Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520, USA and 11 Department of Experimental Medicine and Pathology, La Sapienza University, Rome, Italy
* To whom correspondence should be addressed at:, Mount Sinai School of Medicine, 1425 Madison Ave, PO Box 1498, New York, NY 10029, USA. Tel: +1 2126596744; Fax: +1 2128492638; Email: john.martignetti{at}mssm.edu
Received December 27, 2006; Accepted March 13, 2007
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.
Present address: Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH 44106, USA.
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