Homozygous Dkk1 Knockout Mice Exhibit High Bone Mass Phenotype Due to Increased Bone Formation
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Wnt antagonist Dkk1 is a negative regulator of bone formation and Dkk1 +/− heterozygous mice display a high bone mass phenotype. Complete loss of Dkk1 function disrupts embryonic head development. Homozygous Dkk1 −/− mice that were heterozygous for Wnt3 loss of function mutation (termed Dkk1 KO) are viable and allowed studying the effects of homozygous inactivation of Dkk1 on bone formation. Dkk1 KO mice showed a high bone mass phenotype exceeding that of heterozygous mice as well as a high incidence of polydactyly and kinky tails. Whole body bone density was increased in the Dkk1 KO mice as shown by longitudinal dual-energy X-ray absorptiometry. MicroCT analysis of the distal femur revealed up to 3-fold increases in trabecular bone volume and up to 2-fold increases in the vertebrae, compared to wild type controls. Cortical bone was increased in both the tibiae and vertebrae, which correlated with increased strength in tibial 4-point bending and vertebral compression tests. Dynamic histomorphometry identified increased bone formation as the mechanism underlying the high bone mass phenotype in Dkk1 KO mice, with no changes in bone resorption. Mice featuring only Wnt3 heterozygosity showed no evident bone phenotype. Our findings highlight a critical role for Dkk1 in the regulation of bone formation and a gene dose-dependent response to loss of DKK1 function. Targeting Dkk1 to enhance bone formation offers therapeutic potential for osteoporosis.
KeywordsDkk1 Wnt-signalling Bone High bone mass Knockout model
Compliance with Ethical Standards
Conflict of interest
Drs. Aaron Schindeler and David G. Little report grants and non-financial support from Novartis Pharma, grants from N8 Medical, grants from Celgene, grants and non-financial support from Amgen Inc, outside the submitted work. Dr. Peter I. Croucher reports non-financial support from Novartis Pharma and grants from Amgen Inc outside the submitted work. Dr. Tegan Cheng receives financial support from Hyundai Help for Kids. Michelle M. McDonald, Alyson Morse, Kathy Mikulec, Lauren Peacock, Justin Bobyn, Lucinda Lee, Paul A. Baldock, and Patrick P. L. Tam declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
No patients or patient samples were used in this study. Animal studies were approved by the Southwestern Area Health Service Animal Ethics Committee (AEC) and The Children’s Hospital at Westmead/Children’s Medical Research Institute AEC.
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