title: In vivo impact of a 4 bp deletion mutation in the DLX3 gene on bone development.
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.
authors.affiliation: Human Craniofacial Genetics Section, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20854, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Choi
authors.forename: G D
authors.initials: GD
authors.lastname: Roodman
authors.forename: J Q
authors.initials: JQ
authors.lastname: Feng
authors.forename: I S
authors.initials: IS
authors.lastname: Song
authors.forename: K
authors.initials: K
authors.lastname: Amin
authors.forename: P S
authors.initials: PS
authors.lastname: Hart
authors.forename: J T
authors.initials: JT
authors.lastname: Wright
authors.forename: N
authors.initials: N
authors.lastname: Haruyama
authors.forename: T C
authors.initials: TC
authors.lastname: Hart
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D020029:Base Pairing / Q000235:genetics*; D001846:Bone Development / Q000187:drug effects / Q000235:genetics*; D001862:Bone Resorption / Q000378:metabolism; D005121:Extremities; D005269:Femur / Q000033:anatomy & histology / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics*; D007371:Interferon-gamma / Q000097:blood; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009500:Neutralization Tests; D009929:Organ Size / Q000187:drug effects; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics*; D055114:X-Ray Microtomography
chemical_list: D000906:Antibodies; C088334:Distal-less homeobox proteins; D018398:Homeodomain Proteins; D050505:Mutant Proteins; D014157:Transcription Factors; D007371:Interferon-gamma