In vivo impact of a 4 bp deletion mutation in the DLX3 gene on bone development

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2008.10.014 Byline: S.J. Choi (a), G.D. Roodman (b), J.Q. Feng (c), I.S. Song (a), K. Amin (a), P.S. Hart (d), J.T. Wright (e), N. Haruyama (f), T.C. Hart (a) Keywords: Rodent; Transgenic mice; DLX3; Osteoclast; Bone mineralization; Interferon-gamma Abstract: Distal-less 3 (DLX3) gene mutations are etiologic for Tricho-Dento-Osseous syndrome. To investigate the in vivo impact of mutant DLX3 on bone development, we established transgenic (TG) mice expressing the c.571_574delGGGG DLX-3 gene mutation (MT-DLX3) driven by a mouse 2.3 Col1A1 promoter. Microcomputed tomographic analyses demonstrated markedly increased trabecular bone volume and bone mineral density in femora from TG mice. In ex vivo experiments, TG mice showed enhanced differentiation of bone marrow stromal cells to osteoblasts and increased expression levels of bone formation markers. However, TG mice did not show enhanced dynamic bone formation rates in in vivo fluorochrome double labeling experiments. Osteoclastic differentiation capacities of bone marrow monocytes were reduced in TG mice in the presence of osteoclastogenic factors and the numbers of TRAP(+) osteoclasts on distal metaphyseal trabecular bone surfaces were significantly decreased. TRACP 5b and CTX serum levels were significantly decreased in TG mice, while IFN-[gamma] levels were significantly increased. These data demonstrate that increased levels of IFN-[gamma] decrease osteoclast bone resorption activities, contributing to the enhanced trabecular bone volume and mineral density in these TG mice. These data suggest a novel role for this DLX-3 mutation in osteoclast differentiation and bone resorption. Author Affiliation: (a) Human Craniofacial Genetics Section, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20854, USA (b) Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh, Pittsburgh, PA, USA (c) Biomedical Sciences, Baylor College of Dentistry, Texas A&M Health Science Center, Dallas, TX, USA (d) Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA (e) Department of Pediatric Dentistry, University of North, Chapel Hill, NC, USA (f) Division of Oral Dysfunction Science, Tohoku University, Graduate School of Dentistry, Sendai, Japan Article History: Received 1 August 2008; Revised 5 September 2008; Accepted 2 October 2008