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J. Biol. Chem., Vol. 280, Issue 7, 6197-6203, February 18, 2005

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Dmp1-deficient Mice Display Severe Defects in Cartilage Formation Responsible for a Chondrodysplasia-like Phenotype^*

Ling Ye, Yuji Mishina¶, Di Chen||, Haiyang Huang**, Sarah L. Dallas, Mark R. Dallas, Pitchumani Sivakumar, Tetsuo Kunieda¶¶¶, Takeo W. Tsutsui¶, Adele Boskey, Lynda F. Bonewald, and Jian Q. Feng

From the Department of Oral Biology, School of Dentistry, University of Missouri-Kansas City, Kansas City, Missouri 64108, the ^¶Laboratory of Reproductive and Developmental Toxicology, NIEHS, National Institutes of Health Research Triangle Park, North Carolina 27709, the ^||Department of Orthopaedics, University of Rochester, School of Medicine and Dentistry, Rochester, New York 14642, the ^**Department of Orthopaedic Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China, and the Department of Biochemistry, Hospital for Special Surgery, New York, New York 10021

Understanding the molecular mechanisms by which cartilage formation is regulated is essential toward understanding the physiology of both embryonic bone development and postnatal bone growth. Although much is known about growth factor signaling in cartilage formation, the regulatory role of noncollagenous matrix proteins in this process are still largely unknown. In the present studies, we present evidence for a critical role of DMP1 (dentin matrix protein 1) in postnatal chondrogenesis. The Dmp1 gene was originally identified from a rat incisor cDNA library and has been shown to play an important role in late stage dentinogenesis. Whereas no apparent abnormalities were observed in prenatal bone development, Dmp1-deficient (Dmp1^-/-) mice unexpectedly develop a severe defect in cartilage formation during postnatal chondrogenesis. Vertebrae and long bones in Dmp1-deficient (Dmp1^-/-) mice are shorter and wider with delayed and malformed secondary ossification centers and an irregular and highly expanded growth plate, results of both a highly expanded proliferation and a highly expanded hypertrophic zone creating a phenotype resembling dwarfism with chondrodysplasia. This phenotype appears to be due to increased cell proliferation in the proliferating zone and reduced apoptosis in the hypertrophic zone. In addition, blood vessel invasion is impaired in the epiphyses of Dmp1^-/- mice. These findings show that DMP1 is essential for normal postnatal chondrogenesis and subsequent osteogenesis.

Received for publication, November 15, 2004

^* This work was supported in part by National Institutes of Health Grants DE13480, DE00455, and AR51587 (to J. Q. F.) and AR46798 (to L. F. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

^¶¶ Present address: Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan.

To whom correspondence should be addressed: Dept. of Oral Biology, School of Dentistry, University of Missouri-Kansas City, 650 E. 25th St., Kansas City, MO 64108. Tel.: 816-235-5824; Fax: 816-235-5524; E-mail: fengj{at}umkc.edu.

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