Low peak bone mass and attenuated anabolic response to parathyroid hormone in mice with an osteoblast-specific deletion of connexin43.
Connexin43 (Cx43) is involved in bone development, but its role in adult bone homeostasis remains unknown. To overcome the postnatal lethality of Cx43 null mutation, we generated mice with selective osteoblast ablation of Cx43, obtained using a Cx43fl allele and a 2.3-kb fragment of the alpha1(I) collagen promoter to drive Cre in osteoblasts (ColCre). Conditionally osteoblast-deleted ColCre;Cx43-/fl mice show no malformations at birth, but develop low peak bone mass and remain osteopenic with age, exhibiting reduced bone formation and defective osteoblast function. By both radiodensitometry and histology, bone mineral content increased rapidly and progressively in adult Cx43+/fl mice after subcutaneous injection of parathyroid hormone (PTH), an effect significantly attenuated in ColCre;Cx43-/fl mice, with Cx43-/fl exhibiting an intermediate response. Attenuation of PTH anabolic action was associated with failure to increase mineral apposition rate in response to PTH in ColCre;Cx43-/fl, despite an increased osteoblast number, suggesting a functional defect in Cx43-deficient bone-forming cells. In conclusion, lack of Cx43 in osteoblasts leads to suboptimal acquisition of peak bone mass, and hinders the bone anabolic effect of PTH. Cx43 represents a potential target for modulation of bone anabolism.
Chung
Dong Jin
DJ
Division of Bone and Mineral Diseases, Washington University School of Medicine, 660 S. Euclid Avenue, St Louis, MO 63110, USA.
Castro
Charlles H M
CH
Watkins
Marcus
M
Stains
Joseph P
JP
Chung
Min Young
MY
Szejnfeld
Vera Lucia
VL
Willecke
Klaus
K
Theis
Martin
M
Civitelli
Roberto
R
D000818:Animals; D015153:Blotting, Western; D015519:Bone Density / Q000235:genetics* / Q000502:physiology; D001842:Bone and Bones / Q000002:abnormalities / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D018031:Connexin 43 / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D017629:Gap Junctions / Q000378:metabolism; D017353:Gene Deletion; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D010281:Parathyroid Hormone / Q000494:pharmacology*; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018031:Connexin 43; D010281:Parathyroid Hormone