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Contributions of Dickkopf-1 to Obesity-Induced Bone Loss and Marrow Adiposity.

ABSTRACT: Low bone strength in overweight individuals is a significant medical problem. One important determinant of mesenchymal stem cell fate into osteoblasts or adipocytes is the Wnt signaling pathway. We recently showed that Dickkopf-1 (DKK1), a potent Wnt inhibitor, is upregulated in obese mice. In this study, we investigated the role of DKK1 in the pathogenesis of obesity-induced bone loss using global and tissue-specific KO mice. Obesity was induced in 8-week-old male mice with an inducible global (Rosa26-CreERT2) or osteoprogenitor- (Osx-Cre-) specific deletion of Dkk1 with a high-fat diet (HFD) containing 60% fat. After 12?weeks, body weight, bone volume, bone fat mass, and bone turnover were assessed. Dkk1 ^fl/fl ;Rosa26-CreERT2 mice experienced a similar increase in body weight and white fat pads as control mice. A HFD significantly reduced trabecular bone mass and the bone formation rate in Cre- mice and Dkk1 ^fl/fl ;Rosa26-CreERT2 mice. Interestingly, Dkk1 ^fl/fl ;Rosa26-CreERT2 mice were protected from HFD-induced cortical bone loss. Furthermore, a HFD was associated with increased bone marrow fat in the femur, which was less pronounced in Dkk1 ^fl/fl ;Rosa26-CreERT2 mice. Mice with an osteoprogenitor-specific Dkk1 deletion showed similar results as the global knockout, showing a protection against HFD-induced cortical bone loss and an accumulation of bone marrow fat, but a similar decrease in trabecular bone volume. In summary, DKK1 appears to contribute distinctly to cortical, but not trabecular bone loss in obesity. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

SUBMITTER: Colditz J

PROVIDER: S-EPMC7285751 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Contributions of Dickkopf-1 to Obesity-Induced Bone Loss and Marrow Adiposity.

Colditz Juliane J Picke Ann-Kristin AK Hofbauer Lorenz C LC Rauner Martina M

JBMR plus 20200428 6

Low bone strength in overweight individuals is a significant medical problem. One important determinant of mesenchymal stem cell fate into osteoblasts or adipocytes is the Wnt signaling pathway. We recently showed that Dickkopf-1 (DKK1), a potent Wnt inhibitor, is upregulated in obese mice. In this study, we investigated the role of DKK1 in the pathogenesis of obesity-induced bone loss using global and tissue-specific KO mice. Obesity was induced in 8-week-old male mice with an inducible global ...[more]

PMID: 32537550

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Project description:IntroductionLongitudinal effect of diet-induced obesity on bone is uncertain. Prior work showed both no effect and a decrement in bone density or quality when obesity begins prior to skeletal maturity. We aimed to quantify long-term effects of obesity on bone and bone marrow adipose tissue (BMAT) in adulthood.MethodsSkeletally mature, female C57BL/6 mice (n = 70) aged 12 weeks were randomly allocated to low-fat diet (LFD; 10% kcal fat; n = 30) or high-fat diet (HFD; 60% kcal fat; n = 30), with analyses at 12, 15, 18, and 24 weeks (n = 10/group). Tibial microarchitecture was analyzed by µCT, and volumetric BMAT was quantified via 9.4T MRI/advanced image analysis. Histomorphometry of adipocytes and osteoclasts, and qPCR were performed.ResultsBody weight and visceral white adipose tissue accumulated in response to HFD started in adulthood. Trabecular bone parameters declined with advancing experimental age. BV/TV declined 22% in LFD (p = 0.0001) and 17% in HFD (p = 0.0022) by 24 weeks. HFD failed to appreciably alter BV/TV and had negligible impact on other microarchitecture parameters. Both dietary intervention and age accounted for variance in BMAT, with regional differences: distal femoral BMAT was more responsive to diet, while proximal femoral BMAT was more attenuated by age. BMAT increased 60% in the distal metaphysis in HFD at 18 and 24 weeks (p = 0.0011). BMAT in the proximal femoral diaphysis, unchanged by diet, decreased 45% due to age (p = 0.0002). Marrow adipocyte size via histomorphometry supported MRI quantification. Osteoclast number did not differ between groups. Tibial qPCR showed attenuation of some adipose, metabolism, and bone genes. A regulator of fatty acid β-oxidation, cytochrome C (CYCS), was 500% more abundant in HFD bone (p < 0.0001; diet effect). CYCS also increased due to age, but to a lesser extent. HFD mildly increased OCN, TRAP, and SOST.ConclusionsLong-term high fat feeding after skeletal maturity, despite upregulation of visceral adiposity, body weight, and BMAT, failed to attenuate bone microarchitecture. In adulthood, we found aging to be a more potent regulator of microarchitecture than diet-induced obesity.

Project description:Oxidative stress-induced reactive oxygen species, DNA damage, apoptosis, and cellular senescence have been associated with reduced osteoprogenitors in a reciprocal fashion to bone marrow adipocyte tissue (BMAT); however, a direct (causal) link between cellular senescence and BMAT is still elusive. Accumulation of senescent cells occur in naturally aged and in focally radiated bone tissue, but despite amelioration of age- and radiation-associated bone loss after senescent cell clearance, molecular events that precede BMAT accrual are largely unknown. Here we show by RNA-Sequencing data that BMAT-related genes were the most upregulated gene subset in radiated bones of C57BL/6 mice. Using focal radiation as a model to understand age-associated changes in bone, we performed a longitudinal assessment of cellular senescence and BMAT. Using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), RNA in situ hybridization of p21 transcripts and histological assessment of telomere dysfunction as a marker of senescence, we observed an increase in senescent cell burden of bone cells from day 1 postradiation, without the presence of BMAT. BMAT was significantly elevated in radiated bones at day 7, confirming the qRT-PCR data in which most BMAT-related genes were elevated by day 7, and the trend continued until day 42 postradiation. Similarly, elevation in BMAT-related genes was observed in bones of aged mice. The senolytic cocktail of Dasatinib (D) plus Quercetin (Q) (ie, D + Q), which clears senescent cells, reduced BMAT in aged and radiated bones. MicroRNAs (miRNAs or miRs) linked with senescence marker p21 were downregulated in radiated and aged bones, whereas miR-27a, a miR that is associated with increased BMAT, was elevated both in radiated and aged bones. D + Q downregulated miR-27a in radiated bones at 42 days postradiation. Overall, our study provides evidence that BMAT occurrence in oxidatively stressed bone environments, such as radiation and aging, is induced following a common pathway and is dependent on the presence of senescent cells. © 2022 American Society for Bone and Mineral Research (ASBMR).

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Contributions of Dickkopf-1 to Obesity-Induced Bone Loss and Marrow Adiposity.

Publications

Contributions of Dickkopf-1 to Obesity-Induced Bone Loss and Marrow Adiposity.

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