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Effects of dietary restriction on appendicular bone in the SENCAR mouse
E J Brochmann Murray1, W G Beamer, M E Duarte
1Geriatric Research, Education and Clinical Center, Veterans Affairs Greater Los Angeles Healthcare System, Sepulveda, CA 91343, USA.
Abstract:
Peptide hormones, cytokines, and growth factors regulate cellular metabolism by stimulating second messenger signal transduction cascades in target tissues. A mutation in the regulatory domain of protein kinase C (PKC) in SENCAR (sensitive to carcinogenesis) mice renders them extremely sensitive to diacylglycerol and phorbol esters, resulting in rapid growth, high free radical generation, carcinogenesis, and metabolic bone disease. Dietary restriction (DR) normalizes PKC and ameliorates adverse downstream effects, including carcinogenesis, in SENCAR mice. We hypothesized that DR sufficient to ameliorate carcinogenesis would prevent or delay the early onset of metabolic bone disease in SENCAR mice. Male mice were assigned to 1 of 4 feeding groups from 10 to 16 weeks of age (the critical period when metabolic bone disease develops): ad libitum (AL)-fed; AL antioxidant (0.07% thioproline)-fed; 40% DR; or 40% DR antioxidant-fed. Femoral bone mass was determined gravimetrically. Tibial total, cortical, and trabecular bone mineral density (BMD) were determined by quantitative computed tomography. Body weight, femoral bone mass, and tibial cortical BMD were lower in DR than in AL mice. However, tibial total and trabecular BMD were higher in DR than in AL mice. Serum calcitonin, the hormone that inhibits the osteoclastic bone resorption that is most notable in trabecular bone, was 2-fold higher in DR than in AL-fed mice. Dietary thioproline had no major effects. Thus, DR sufficient to ameliorate carcinogenesis in SENCAR mice did not prevent early-onset metabolic bone disease, but it had a beneficial effect on tibial trabecular BMD that occurred at the apparent expense of cortical BMD. DR in SENCAR mice was also associated with elevated serum calcitonin, which may inhibit osteoclastic resorption and account for trabecular bone conservation in this model. In conclusion, PKC or the downstream metabolic processes regulated by it appear to play previously unrecognized roles in the regulation of tibial trabecular BMD and serum calcitonin in SENCAR mice.
Insights
Dietary restriction in SENCAR mice did not prevent metabolic bone disease but improved trabecular bone density. This dietary intervention also increased serum calcitonin, suggesting a role for protein kinase C in bone regulation.
Area of Science:
- Cellular Metabolism
- Carcinogenesis
- Bone Biology
Background:
- Protein kinase C (PKC) mutations in SENCAR mice cause sensitivity to diacylglycerol and phorbol esters, leading to rapid growth, carcinogenesis, and metabolic bone disease.
- Dietary restriction (DR) normalizes PKC and ameliorates carcinogenesis in these mice.
- The study investigated if DR could prevent or delay metabolic bone disease onset in SENCAR mice.
Purpose of the Study:
- To determine if dietary restriction (DR) prevents or delays early-onset metabolic bone disease in SENCAR mice.
- To assess the effects of DR on bone mass, bone mineral density (BMD), and serum calcitonin levels.
- To explore the role of protein kinase C (PKC) in metabolic bone disease and bone regulation.
Main Methods:
- Male SENCAR mice were assigned to ad libitum (AL) or 40% DR feeding groups from 10 to 16 weeks of age.
- Some groups received antioxidants (thioprolin).
- Femoral bone mass, tibial total, cortical, and trabecular BMD, and serum calcitonin were measured.
Main Results:
- DR mice had lower body weight, femoral bone mass, and tibial cortical BMD compared to AL mice.
- Tibial total and trabecular BMD were higher in DR mice.
- Serum calcitonin was significantly elevated in DR mice, potentially inhibiting osteoclastic bone resorption.
Conclusions:
- DR sufficient to ameliorate carcinogenesis did not prevent early-onset metabolic bone disease in SENCAR mice.
- DR beneficially affected tibial trabecular BMD at the expense of cortical BMD.
- Elevated serum calcitonin in DR mice may contribute to trabecular bone conservation, indicating a role for PKC in regulating tibial trabecular BMD and calcitonin levels.