Article
Apolipoprotein E (apoE) isoforms influence bone mass and turnover in vivo
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Published: | October 18, 2011 |
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Questionnaire: We have previously shown that apoE -/- mice display a high bone mass phenotype due to an increased bone formation rate and that apoE inhibits murine and human osteoblasts differentiation and function through inhibition of canonical wnt signaling. Mice have only one form of apoE and do not express isoforms, while in humans, three isoforms of apoE (E2, E3, E4) exist. The isoforms differentially affect lipoprotein metabolism and apoE4 is a well established risk factor for Alzheimer's disease, while the expression of apoE2 is associated with the development of hyperlipidemia and coronary artery disease. A substantial body of literature has been published on the question whether or not the apoE isoforms have a differential impact on bone mineral density and fracture incidence, but the issue remains highly controversial. Part of the reason for this controversy is the asymmetric allele frequency of the apoE gene (ε2=0.08, ε3=0.77, ε4=0.15) which renders human studies very difficult to perform. We therefore addressed the question whether human apoE isoforms have an impact on bone with so-called “apoE knock-in” (apoE k.i.) mice that have been genetically modified to express the human apoE2, E3 and E4 isoforms instead of the murine apoE.
Methods: Biochemical serum and urinary bone turnover markers (osteocalcin, alkaline phosphatase, osteoprotegerin, RANKL and DPD crosslinks) were measured with standard procedures. 12-week old female animals (n=8 per group) were sacrificed and the skeletal status was assessed by conventional X-ray, µCT and histomorphometrical analyses.
Results and Conclusions: ApoE2 k.i. animals, as compared to apoE3 k.i. and apoE4 k.i. displayed a significantly increased concentration of serum RANKL with decreased OPG / RANKL ratio and, correspondingly, a significantly reduced lumbar trabecular bone mass (BV/TV, Tb. N.) due to a significantly reduced bone formation rate (BFR). In contrast, apoE4 animals, as compared to apoE2 and E3, displayed a significantly lower concentration of serum osteocalcin and urinary DPD, indicating low bone turnover. In contrast to E2, apoE4 animals displayed a lumbar trabecular bone mass comparable to E3 animals, but a significantly smaller femur cortical thickness.
In conclusion, this study provides the first unequivocal genetic evidence that the human apoE isoforms E2, E3 and E4 differentially affect bone turnover and bone mass in vivo. At present, we do not understand yet by which mechanisms the isoform-specific differences can be explained, but the current data strongly underline the general importance of apoE as a gene that regulates bone metabolism.