Dlx5, a positive regulator of osteoblastogenesis, is essential for osteoblast-osteoclast coupling.
The homeodomain protein Dlx5 is an activator of Runx2 (a key regulator of osteogenesis) and is thought to be an important regulator of bone formation. At present, however, the perinatal lethality of Dlx5-null mice has hampered the elucidation of its function in osteogenesis. Here we provide the first analysis of the effects of Dlx5 inactivation on bone development. Femurs of Dlx5-null mouse embryos at the end of gestation exhibit a reduction in both total and trabecular bone volume associated with increased trabecular separation and reduced trabecular number. These parameters are often associated with pathological conditions characterized by reduced osteoblast activity and increased bone resorption. Dlx5(-/-) osteoblasts in culture display reduced proliferation and differentiation rate and reduction of Runx2, Osx, Osteocalcin and Bone Sialoprotein expression. In addition to impaired osteoblast function, Dlx5(-/-) femurs exhibit significant increases in osteoclast number. As Dlx5 is not expressed by osteoclasts, we suggest that its osteoblastic expression might control osteoblast/osteoclast coupling. Cultured Dlx5(-/-) osteoblasts displayed a higher RANKL/OPG ratio. Furthermore, Dlx5(-/-) osteoblasts induced a higher number of TRAP-positive multinucleated cells in normal spleen cultures with a globally increased resorption activity. These findings suggest that Dlx5 is a central regulator of bone turnover as it activates bone formation directly and bone resorption indirectly.
Samee
Nadeem
N
INSERM U606, Hôpital Lariboisière, Paris, France.
Geoffroy
Valerie
V
Marty
Caroline
C
Schiltz
Corinne
C
Vieux-Rochas
Maxence
M
Levi
Giovanni
G
de Vernejoul
Marie-Christine
MC
D000818:Animals; D001846:Bone Development / Q000502:physiology*; D001862:Bone Resorption / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D050659:Core Binding Factor Alpha 1 Subunit / Q000096:biosynthesis; D004622:Embryo, Mammalian; D005269:Femur / Q000166:cytology / Q000196:embryology; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000378:metabolism*; D007150:Immunohistochemistry; D058574:Integrin-Binding Sialoprotein; D051379:Mice; D008817:Mice, Mutant Strains; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D015675:Osteocalcin / Q000096:biosynthesis; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology*; D053244:Osteoprotegerin / Q000096:biosynthesis; D053245:RANK Ligand / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000096:biosynthesis; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000096:biosynthesis
D050659:Core Binding Factor Alpha 1 Subunit; C501120:Dlx5 protein, mouse; D018398:Homeodomain Proteins; C546872:Ibsp protein, mouse; D058574:Integrin-Binding Sialoprotein; D053244:Osteoprotegerin; D053245:RANK Ligand; C493716:Runx2 protein, mouse; D012795:Sialoglycoproteins; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D014157:Transcription Factors; D015675:Osteocalcin