High bone resorption in adult aging transgenic mice overexpressing cbfa1/runx2 in cells of the osteoblastic lineage
- PMID: 12167715
- PMCID: PMC134019
- DOI: 10.1128/MCB.22.17.6222-6233.2002
High bone resorption in adult aging transgenic mice overexpressing cbfa1/runx2 in cells of the osteoblastic lineage
Abstract
The runt family transcription factor core-binding factor alpha1 (Cbfa1) is essential for bone formation during development. Surprisingly, transgenic mice overexpressing Cbfa1 under the control of the 2.3-kb collagen type I promoter developed severe osteopenia that increased progressively with age and presented multiple fractures. Analysis of skeletally mature transgenic mice showed that osteoblast maturation was affected and that specifically in cortical bone, bone resorption as well as bone formation was increased, inducing high bone turnover rates and a decreased degree of mineralization. To understand the origin of the increased bone resorption, we developed bone marrow stromal cell cultures and reciprocal coculture of primary osteoblasts and spleen cells from wild-type or transgenic mice. We showed that transgenic cells of the osteoblastic lineage induced an increased number of tartrate-resistant acid phosphatase-positive multinucleated cells, suggesting that primary osteoblasts as well as bone marrow stromal cells from transgenic mice have stronger osteoclastogenic properties than cells derived from wild-type animals. We investigated the candidate genes whose altered expression could trigger this increase in bone resorption, and we found that the expression of receptor activator of NF-kappaB ligand (RANKL) and collagenase 3, two factors involved in bone formation-resorption coupling, was markedly increased in transgenic cells. Our data thus suggest that overexpression of Cbfa1 in cells of the osteoblastic lineage does not necessarily induce a substantial increase in bone formation in the adult skeleton but has a positive effect on osteoclast differentiation in vitro and can also dramatically enhance bone resorption in vivo, possibly through increased RANKL expression.
Figures
Similar articles
-
Aging increases stromal/osteoblastic cell-induced osteoclastogenesis and alters the osteoclast precursor pool in the mouse.J Bone Miner Res. 2005 Sep;20(9):1659-68. doi: 10.1359/JBMR.050503. Epub 2005 May 2. J Bone Miner Res. 2005. PMID: 16059637
-
The osteoblast-specific transcription factor Cbfa1 contributes to the expression of osteoprotegerin, a potent inhibitor of osteoclast differentiation and function.J Biol Chem. 2000 Aug 18;275(33):25163-72. doi: 10.1074/jbc.M000322200. J Biol Chem. 2000. PMID: 10833509
-
Inflammatory T cells rapidly induce differentiation of human bone marrow stromal cells into mature osteoblasts.J Cell Biochem. 2003 Mar 1;88(4):650-9. doi: 10.1002/jcb.10436. J Cell Biochem. 2003. PMID: 12577299
-
Regulatory mechanisms of osteoblast and osteoclast differentiation.Oral Dis. 2002 May;8(3):147-59. doi: 10.1034/j.1601-0825.2002.01829.x. Oral Dis. 2002. PMID: 12108759 Review.
-
Osteoprotegerin: a physiological and pharmacological inhibitor of bone resorption.Curr Pharm Des. 2001 May;7(8):613-35. doi: 10.2174/1381612013397807. Curr Pharm Des. 2001. PMID: 11375772 Review.
Cited by
-
Wnt signaling in periodontitis.Clin Oral Investig. 2023 Nov;27(11):6801-6812. doi: 10.1007/s00784-023-05294-7. Epub 2023 Oct 10. Clin Oral Investig. 2023. PMID: 37814163
-
Peptidylarginine deiminase 2 plays a key role in osteogenesis by enhancing RUNX2 stability through citrullination.Cell Death Dis. 2023 Aug 30;14(8):576. doi: 10.1038/s41419-023-06101-7. Cell Death Dis. 2023. PMID: 37648716 Free PMC article.
-
CK1α/RUNX2 Axis in the Bone Marrow Microenvironment: A Novel Therapeutic Target in Multiple Myeloma.Cancers (Basel). 2022 Aug 29;14(17):4173. doi: 10.3390/cancers14174173. Cancers (Basel). 2022. PMID: 36077711 Free PMC article.
-
Bone Disease in Multiple Myeloma: Biologic and Clinical Implications.Cells. 2022 Jul 27;11(15):2308. doi: 10.3390/cells11152308. Cells. 2022. PMID: 35954151 Free PMC article. Review.
-
miR-23b mediates TNF-α-Inhibited Osteogenic Differentiation of Human Periodontal Ligament Stem Cells by Targeting Runx2.Int J Med Sci. 2021 Sep 9;18(16):3674-3683. doi: 10.7150/ijms.64312. eCollection 2021. Int J Med Sci. 2021. PMID: 34790039 Free PMC article.
References
-
- Aubin, J. E. 1998. Bone stem cells. J. Cell. Biochem. 31:73-82. - PubMed
-
- Beamer, W. G., L. R. Donahue, C. J. Rosen, and D. J. Baylink. 1996. Genetic variability in adult bone density among inbred strains of mice. Bone 18:397-403. - PubMed
-
- Bedalov, A., R. Salvatori, M. Dodig, M. S. Kronenberg, B. Kapural, Z. Bogdanovic, B. E. Kream, C. O. Woody, S. H. Clark, K. Mack, D. W. Rowe, and A. C. Lichtler. 1995. Regulation of COL1A1 expression in type I collagen-producing tissues: identification of a 49 base pair region which is required for transgene expression in bone of transgenic mice. J. Bone Miner. Res. 10:1443-1451. - PubMed
-
- Benson, M. D., J. E. Aubin, G. Xiao, P. E. Thomas, and R. T. Franceschi. 1999. Cloning of a 2.5 kb murine bone sialoprotein promoter fragment and functional analysis of putative Osf2 binding sites. J. Bone Miner. Res. 14:396-405. - PubMed
-
- Bogdanovic, Z., A. Bedalov, P. H. Krebsbach, D. Pavlin, C. O. Woody, S. H. Clark, H. F. Thomas, D. W. Rowe, B. E. Kream, and A. C. Lichtler. 1994. Upstream regulatory elements necessary for expression of the rat COL1A1 promoter in transgenic mice. J. Bone Miner. Res. 9:285-292. - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases