Col3.6-HSD2 transgenic mice: A glucocorticoid loss-of-function model spanning early and late osteoblast differentiation |
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| Authors: | Maobin Yang Lorin B. Trettel Douglas J. Adams John R. Harrison Ernesto Canalis Barbara E. Kream |
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| Affiliation: | 1. USDA ARS Grand Forks Human Nutrition Research Center, Grand Forks, ND, United States;2. Department of Neuroscience & Regenerative Medicine, Georgia Regents University, Augusta, GA, United States;3. Department of Medicine, University of Connecticut Health Center, Farmington, CT, United States;4. Department of Cell Biology, Georgia Regents University, Augusta, GA, United States;5. Department of Orthopaedic Surgery, Georgia Regents University, Augusta, GA, United States;1. ICATME-Hospital Universitari Quirón-Dexeus, Universitat Autònoma de Barcelona, Sabino de Arana 5–19, 08028 Barcelona, Spain;2. Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Sant Quintí 89, 08041 Barcelona, Spain;3. Centro Artroscópico Jorge Batista S.A., Pueyrredón 2446 5° B, C1119ACU Ciudad Autónoma de Buenos Aires, Argentina;4. Parc de Salut Mar, Universitat Autònoma de Barcelona, Passeig Marítim 25, 08003 Barcelona, Spain;1. MIMR-PHI Institute of Medical Research, Clayton, VIC, Australia;2. Department of Human Biosciences, La Trobe University, Bundoora, VIC, Australia;3. Barwon Biomedical Research, Department of Medicine, The Geelong Hospital, Geelong, VIC, Australia;4. School of Medicine, Deakin University, Geelong, VIC, Australia;5. Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia;6. Department of Orthopaedics, St Vincent''s Hospital, Fitzroy, VIC, Australia;7. Department of Surgery, St Vincent''s Hospital, Fitzroy, VIC, Australia;1. Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States;2. Centre for Bone and Arthritis Research at Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden;3. Department of Molecular Periodontology, Umeå University, Umeå, Sweden;4. Institute of Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany |
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| Abstract: | The goal of this study was to characterize the bone phenotype and molecular alterations in Col3.6-HSD2 mice in which a 3.6-kb Col1a1 promoter fragment drives 11ß-HSD2 expression broadly in the osteoblast lineage to reduce glucocorticoid signaling. Serum corticosterone was unchanged in transgenic females exluding a systemic effect of the transgene. Adult transgenic mice showed reduced vertebral trabecular bone volume and reduced femoral and tibial sub-periosteal and sub-endosteal areas as assessed by microCT. In adult female transgenic mice, histomorphometry showed that vertebral bone mass and trabecular number were reduced but that osteoblast and osteoclast numbers and the mineral apposition and bone formation rates were not changed, suggesting a possible developmental defect in the formation of trabeculae. In a small sample of male mice, osteoblast number and percent osteoid surface were increased but the mineral apposition bone formation rates were not changed, indicating subtle sex-specific phenotypic differences in Col3.6-HSD2 bone. Serum from transgenic mice had decreased levels of the C-terminal telopeptide of α1(I) collagen but increased levels of osteocalcin. Transgenic calvarial osteoblast and bone marrow stromal cultures showed decreased alkaline phosphatase and mineral staining, reduced levels of Col1a1, bone sialoprotein and osteocalcin mRNA expression, and decreased cell growth and proliferation. Transgenic bone marrow cultures treated with RANKL and M-CSF showed greater osteoclast formation; however, osteoclast activity as assessed by resorption of a calcium phosphate substrate was decreased in transgenic cultures. Gene profiling of cultured calvarial osteoblasts enriched in the Col3.6-HSD2 transgene showed modest but significant changes in gene expression, particularly in cell cycle and integrin genes. In summary, Col3.6-HSD2 mice showed a low bone mass phenotype, with decreased ex vivo osteogenesis. These data further strengthen the concept that endogenous glucocorticoid signaling is required for optimal bone mass acquisition and highlight the complexities of glucocorticoid signaling in bone cell lineages. |
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