{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T11:51:56Z","timestamp":1789213916836,"version":"build-2803163510"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2008,12,1]],"date-time":"2008-12-01T00:00:00Z","timestamp":1228089600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The Brtl mouse, a knock-in model for moderately severe osteogenesis imperfecta (OI), has a G349C substitution in half of type I collagen \u03b11(I) chains. We studied the cellular contribution to Brtl bone properties. Brtl cortical and trabecular bone are reduced before and after puberty, with BV\/TV decreased 40\u201345%. Brtl ObS\/BS is comparable to wildtype, and Brtl and wildtype marrow generate equivalent number of colony-forming units (CFUs) at both ages. However, OcS\/BS is increased in Brtl at both ages (36\u201345%), as are TRACP+ cell numbers (57\u201347%). After puberty, Brtl ObS\/BS decreases comparably to wildtype mice, but osteoblast matrix production (MAR) decreases to one half of wildtype values. In contrast, Brtl OcS falls only moderately (\u223c16%), and Brtl TRACP staining remains significantly elevated compared with wildtype. Consequently, Brtl BFR decreases from normal at 2 mo to one half of wildtype values at 6 mo. Immunohistochemistry and real-time RT-PCR show increased RANK, RANKL, and osteoprotegerin (OPG) levels in Brtl, although a normal RANKL\/OPG ratio is maintained. TRACP+ precursors are markedly elevated in Brtl marrow cultures and form more osteoclasts, suggesting that osteoclast increases arise from more RANK-expressing precursors. We conclude that osteoblasts and osteoclasts are unsynchronized in Brtl bone. This cellular imbalance results in declining BFR as Brtl ages, consistent with reduced femoral geometry. The disparity in cellular number and function results from poorly functioning osteoblasts in addition to increased RANK-expressing precursors that respond to normal RANKL\/OPG ratios to generate more bone-resorbing osteoclasts. Interruption of the stimulus that increases osteoclast precursors may lead to novel OI therapies.<\/jats:p>","DOI":"10.1359\/jbmr.080804","type":"journal-article","created":{"date-parts":[[2008,8,6]],"date-time":"2008-08-06T14:55:15Z","timestamp":1218034515000},"page":"1983-1994","source":"Crossref","is-referenced-by-count":87,"title":["Cellular Mechanism of Decreased Bone in Brtl Mouse Model of OI: Imbalance of Decreased Osteoblast Function and Increased Osteoclasts and Their Precursors"],"prefix":"10.1093","volume":"23","author":[{"given":"Thomas E","family":"Uveges","sequence":"first","affiliation":[{"name":"These authors are co-first authors"},{"name":"Present address: Trevigen, Gaithersburg, Maryland, USA"},{"name":"Bone and Extracellular Matrix Branch, NICHD, NIH, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Collin-Osdoby","sequence":"additional","affiliation":[{"name":"Department of Biology and Division of Bone and Mineral Metabolism, Washington University, St Louis, Missouri, USA"},{"name":"These authors are co-first authors"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wayne A","family":"Cabral","sequence":"additional","affiliation":[{"name":"Bone and Extracellular Matrix Branch, NICHD, NIH, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felicia","family":"Ledgard","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Connecticut Health Center, Farmington, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah","family":"Goldberg","sequence":"additional","affiliation":[{"name":"Department of Biology and Division of Bone and Mineral Metabolism, Washington University, St Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clemens","family":"Bergwitz","sequence":"additional","affiliation":[{"name":"Present address: Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA"},{"name":"Bone and Extracellular Matrix Branch, NICHD, NIH, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Forlino","sequence":"additional","affiliation":[{"name":"Present address: Department of Biochemistry, \u201cA Castellani,\u201d University of Pavia, Pavia, Italy"},{"name":"Bone and Extracellular Matrix Branch, NICHD, NIH, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Osdoby","sequence":"additional","affiliation":[{"name":"Department of Biology and Division of Bone and Mineral Metabolism, Washington University, St Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria A","family":"Gronowicz","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Connecticut Health Center, Farmington, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joan C","family":"Marini","sequence":"additional","affiliation":[{"name":"Bone and Extracellular Matrix Branch, NICHD, NIH, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,12,4]]},"reference":[{"key":"2024020319464667700_bib1","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1002\/0471221929.ch8","volume-title":"Connective Tissue and Its Heritable Disorders","author":"Byers","year":"2002","edition":"2nd ed"},{"key":"2024020319464667700_bib2","first-page":"2336","volume-title":"Nelson Textbook of Pediatrics","author":"Marini","year":"2004","edition":"17th ed"},{"key":"2024020319464667700_bib3","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/S8756-3282(00)00269-6","article-title":"Static and dynamic bone histomorphometry in children with osteogenesis imperfecta","volume":"26","author":"Rauch","year":"2000","journal-title":"Bone"},{"key":"2024020319464667700_bib4","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1359\/jbmr.2003.18.2.237","article-title":"Positive linear growth and bone responses to growth hormone treatment in children with types III and IV osteogenesis imperfecta: High predictive value of the carboxyterminal propeptide of type I procollagen","volume":"18","author":"Marini","year":"2003","journal-title":"J Bone Miner Res"},{"key":"2024020319464667700_bib5","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/304315a0","article-title":"Embryonic lethal mutation in mice induced by retrovirus insertion into the alpha 1(I) collagen gene","volume":"304","author":"Schnieke","year":"1983","journal-title":"Nature"},{"key":"2024020319464667700_bib6","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/332131a0","article-title":"Perinatal lethal osteogenesis imperfecta in transgenic mice bearing an engineered mutant pro-alpha 1(I) collagen gene","volume":"332","author":"Stacey","year":"1988","journal-title":"Nature"},{"key":"2024020319464667700_bib7","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1172\/JCI116252","article-title":"Transgenic mice expressing a partially deleted gene for type I procollagen (COL1A1). A breeding line with a phenotype of spontaneous fractures and decreased bone collagen and mineral","volume":"91","author":"Pereira","year":"1993","journal-title":"J Clin Invest"},{"key":"2024020319464667700_bib8","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1073\/pnas.90.5.1701","article-title":"Defective pro alpha 2(I) collagen synthesis in a recessive mutation in mice: A model of human osteogenesis imperfecta","volume":"90","author":"Chipman","year":"1993","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024020319464667700_bib9","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/S8756-3282(96)00305-5","article-title":"Heterozygous oim mice exhibit a mild form of osteogenesis imperfecta","volume":"19","author":"Saban","year":"1996","journal-title":"Bone"},{"key":"2024020319464667700_bib10","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1210\/endo.143.5.8807","article-title":"Osteoblastic response to the defective matrix in the osteogenesis imperfecta murine (oim) mouse","volume":"143","author":"Kalajzic","year":"2002","journal-title":"Endocrinology"},{"key":"2024020319464667700_bib11","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1086\/420794","article-title":"Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway","volume":"74","author":"Schwarze","year":"2004","journal-title":"Am J Hum Genet"},{"key":"2024020319464667700_bib12","doi-asserted-by":"crossref","first-page":"e36","DOI":"10.1136\/jmg.2005.038224","article-title":"Total absence of the alpha2(I) chain of collagen type I causes a rare form of Ehlers-Danlos syndrome with hypermobility and propensity to cardiac valvular problems","volume":"43","author":"Malfait","year":"2006","journal-title":"J Med Genet"},{"key":"2024020319464667700_bib13","doi-asserted-by":"crossref","first-page":"37923","DOI":"10.1074\/jbc.274.53.37923","article-title":"Use of the Cre\/lox recombination system to develop a non-lethal knock-in murine model for osteogenesis imperfecta with an alpha1(I) G349C substitution. Variability in phenotype in BrtlIV mice","volume":"274","author":"Forlino","year":"1999","journal-title":"J Biol Chem"},{"key":"2024020319464667700_bib14","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1359\/JBMR.040111","article-title":"Brittle IV mouse model for osteogenesis imperfecta IV demonstrates postpubertal adaptations to improve whole bone strength","volume":"19","author":"Kozloff","year":"2004","journal-title":"J Bone Miner Res"},{"key":"2024020319464667700_bib15","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1126\/science.2448875","article-title":"Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase","volume":"239","author":"Saiki","year":"1988","journal-title":"Science"},{"key":"2024020319464667700_bib16","first-page":"75","article-title":"Trichrome stainings and their preliminary techniques","volume":"12","author":"Masson","year":"1929","journal-title":"J Tech Meth"},{"key":"2024020319464667700_bib17","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1002\/jbmr.5650020617","article-title":"Bone histomorphometry: Standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee","volume":"2","author":"Parfitt","year":"1987","journal-title":"J Bone Miner Res"},{"key":"2024020319464667700_bib18","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1007\/s002239900121","article-title":"Species differences in growth requirements for bone marrow stromal fibroblast colony formation In vitro","volume":"59","author":"Kuznetsov","year":"1996","journal-title":"Calcif Tissue Int"},{"key":"2024020319464667700_bib19","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1359\/jbmr.2002.17.2.331","article-title":"Age-related osteoporosis in biglycan-deficient mice is related to defects in bone marrow stromal cells","volume":"17","author":"Chen","year":"2002","journal-title":"J Bone Miner Res"},{"key":"2024020319464667700_bib20","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1007\/BF02411252","article-title":"Bone acid phosphatase: Tartrate-resistant acid phosphatase as a marker of osteoclast function","volume":"34","author":"Minkin","year":"1982","journal-title":"Calcif Tissue Int"},{"key":"2024020319464667700_bib21","doi-asserted-by":"crossref","first-page":"3868","DOI":"10.1002\/art.22253","article-title":"Fcgamma receptors directly mediate cartilage, but not bone, destruction in murine antigen-induced arthritis: Uncoupling of cartilage damage from bone erosion and joint inflammation","volume":"54","author":"van Lent","year":"2006","journal-title":"Arthritis Rheum"},{"key":"2024020319464667700_bib22","doi-asserted-by":"crossref","first-page":"15809","DOI":"10.1074\/jbc.M513225200","article-title":"RANKL stimulates inducible nitric-oxide synthase expression and nitric oxide production in developing osteoclasts. An autocrine negative feedback mechanism triggered by RANKL-induced interferon-beta via NF-kappaB that restrains osteoclastogenesis and bone resorption","volume":"281","author":"Zheng","year":"2006","journal-title":"J Biol Chem"},{"key":"2024020319464667700_bib23","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1002\/jbmr.5650060615","article-title":"Urinary excretion of pyridinoline crosslinks correlates with bone turnover measured on iliac crest biopsy in patients with vertebral osteoporosis","volume":"6","author":"Delmas","year":"1991","journal-title":"J Bone Miner Res"},{"key":"2024020319464667700_bib24","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1002\/ajmg.1320450223","article-title":"Evaluation of growth hormone axis and responsiveness to growth stimulation of short children with osteogenesis imperfecta","volume":"45","author":"Marini","year":"1993","journal-title":"Am J Med Genet"},{"key":"2024020319464667700_bib25","first-page":"27","article-title":"Transforming growth factor-beta gene family members and bone","volume":"15","author":"Centrella","year":"1994","journal-title":"Endocr Rev"},{"key":"2024020319464667700_bib26","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/0092-8674(89)90795-2","article-title":"Retrovirus-induced insertional mutation in Mov13 mice affects collagen I expression in a tissue-specific manner","volume":"57","author":"Kratochwil","year":"1989","journal-title":"Cell"},{"key":"2024020319464667700_bib27","doi-asserted-by":"crossref","first-page":"7145","DOI":"10.1073\/pnas.87.18.7145","article-title":"Transgenic mouse model of the mild dominant form of osteogenesis imperfecta","volume":"87","author":"Bonadio","year":"1990","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024020319464667700_bib28","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1172\/JCI116756","article-title":"A murine skeletal adaptation that significantly increases cortical bone mechanical properties. Implications for human skeletal fragility","volume":"92","author":"Bonadio","year":"1993","journal-title":"J Clin Invest"},{"key":"2024020319464667700_bib29","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1007\/s002239900412","article-title":"Bone geometry and strength measurements in aging mice with the oim mutation","volume":"62","author":"McBride","year":"1998","journal-title":"Calcif Tissue Int"},{"key":"2024020319464667700_bib30","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1002\/pmic.200600919","article-title":"Differential expression of both extracellular and intracellular proteins is involved in the lethal or nonlethal phenotypic variation of BrtlIV, a murine model for osteogenesis imperfecta","volume":"7","author":"Forlino","year":"2007","journal-title":"Proteomics"},{"key":"2024020319464667700_bib31","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1002\/jbmr.5650100224","article-title":"Comment","volume":"10","author":"Shapiro","year":"1995","journal-title":"J Bone Miner Res"},{"key":"2024020319464667700_bib32","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1111\/j.1651-2227.1998.tb00920.x","article-title":"Collagen-derived markers of bone metabolism in osteogenesis imperfecta","volume":"87","author":"Lund","year":"1998","journal-title":"Acta Paediatr"},{"key":"2024020319464667700_bib33","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.molmed.2005.11.007","article-title":"RANKL-RANK signaling in osteoclastogenesis and bone disease","volume":"12","author":"Wada","year":"2006","journal-title":"Trends Mol Med"},{"key":"2024020319464667700_bib34","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1196\/annals.1346.013","article-title":"Regulation of osteoclast differentiation","volume":"1068","author":"Roodman","year":"2006","journal-title":"Ann N Y Acad Sci"},{"key":"2024020319464667700_bib35","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1097\/01.bor.0000231913.32364.32","article-title":"Osteoclast precursors: Cytokine-stimulated immunomodulators of inflammatory bone disease","volume":"18","author":"Boyce","year":"2006","journal-title":"Curr Opin Rheumatol"},{"key":"2024020319464667700_bib36","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1186\/ar1857","article-title":"Osteoclasts; culprits in inflammatory osteolysis","volume":"8","author":"Teitelbaum","year":"2006","journal-title":"Arthritis Res Ther"},{"key":"2024020319464667700_bib37","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1002\/jcb.21337","article-title":"Increased resorptive activity and accompanying morphological alterations in osteoclasts derived from the oim\/oim mouse model of osteogenesis imperfecta","volume":"102","author":"Zhang","year":"2007","journal-title":"J Cell Biochem"}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1359%2Fjbmr.080804","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/23\/12\/1983\/7599386","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/23\/12\/1983\/7599386","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T14:51:21Z","timestamp":1710341481000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/23\/12\/1983-1994\/7599386"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,12,1]]},"references-count":37,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2009,12,4]]},"published-print":{"date-parts":[[2008,12,1]]}},"URL":"https:\/\/doi.org\/10.1359\/jbmr.080804","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2008,12,1]]},"published":{"date-parts":[[2008,12,1]]}}}