High bone resorption in adult aging transgenic mice overexpressing cbfa1/runx2 in cells of the osteoblastic lineage.
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.
Geoffroy
Valérie
V
Friedrich-Miescher Institute for Biomedical Research, Zweigniederlassung Novartis Forschungsstiftung,Basel, Switzerland.
Kneissel
Michaela
M
Fournier
Brigitte
B
Boyde
Alan
A
Matthias
Patrick
P
D000375:Aging / Q000378:metabolism*; D000818:Animals; D015519:Bone Density; D001851:Bone Diseases, Metabolic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000473:pathology; D001857:Bone Matrix / Q000378:metabolism; D001862:Bone Resorption / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage; D002478:Cells, Cultured / Q000378:metabolism / Q000473:pathology; D018920:Coculture Techniques; D003094:Collagen / Q000235:genetics; D017364:Collagenases / Q000096:biosynthesis / Q000235:genetics; D050659:Core Binding Factor Alpha 1 Subunit; D050660:Core Binding Factors; D005260:Female; D005838:Genotype; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D053509:Matrix Metalloproteinase 13; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009363:Neoplasm Proteins; D010006:Osteoblasts / Q000378:metabolism*; D010010:Osteoclasts / Q000473:pathology; D053244:Osteoprotegerin; D011401:Promoter Regions, Genetic; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000502:physiology; D013154:Spleen / Q000473:pathology; D017154:Stromal Cells / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D002352:Carrier Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D050660:Core Binding Factors; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D014157:Transcription Factors; D003094:Collagen; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse