Adverse effects of hyperlipidemia on bone regeneration and strength

Abstract

Hyperlipidemia increases the risk for generation of lipid oxidation products, which accumulate in the subendothelial spaces of vasculature and bone. Atherogenic high-fat diets increase serum levels of oxidized lipids, which are known to attenuate osteogenesis in culture and to promote bone loss in mice. In this study, we investigated whether oxidized lipids affect bone regeneration and mechanical strength. Wild type and hyperlipidemic (Ldlr−/−) mice were placed on a high-fat (HF) diet for 13 weeks. Bilateral cranial defects were introduced on each side of the sagittal suture, and 5 weeks post-surgery on the respective diets, the repair/regeneration of cranial bones and mechanical properties of femoral bones were assessed. MicroCT and histological analyses demonstrated that bone regeneration was significantly impaired by the HF diet in WT and Ldlr−/− mice. In femoral bone, cortical bone volume fraction (BV/TV) was significantly reduced while cortical porosity was increased by the HF diet in Ldlr−/− but not in WT mice. Femoral bone strength and stiffness, measured by three-point bending analysis, were significantly reduced by the HF diet in Ldlr−/−, but not in WT mice. Serum analysis showed that the HF diet significantly increased levels of parathyroid hormone, TNF-alpha, calcium and phosphorus, whereas it reduced procollagen type I N-terminal propeptide, a serum marker of bone formation, in Ldlr−/−, but not in WT mice. The serum level of carboxyl-terminal collagen crosslinks, a marker for bone resorption, was also 1.7-fold greater in Ldlr−/− mice. These findings suggest that hyperlipidemia induces secondary hyperparathyroidism and impairs bone regeneration and mechanical strength.

Skeletal inflammation and attenuation of Wnt signaling, Wnt ligand expression, and bone formation in atherosclerotic ApoE-null mice

“…The latter effect is consistent with a report of increased TNF in serum of HFD-fed LDL receptor-null mice (48). Mice lacking TNF, or functional TNF receptors, exhibit increased bone mass because of increased bone formation (33), indicating that even under normal physiological conditions endogenous TNF restrains bone formation.…”

“…The HFD thus restrained bone acquisition in the earlier work. Consistent with this, bone formation rate is suppressed in growing HFD-fed atherosclerotic LDL receptor-null mice (24,48). Nevertheless, osteoblast number was unchanged, suggesting that the reduced bone mass is due to attenuated osteoblast function in juvenile mice.…”

“…Consistent with the evidence for a linkage between atherosclerosis and osteoporosis in humans, ApoE-null (ApoE-KO) mice or LDL receptor-null mice fed a HFD exhibit reduced bone mass (24,48,49,53). The mass and structural integrity of the skeleton are maintained by teams of osteoclasts and osteoblasts that, respectively, resorb old bone and replace it with new (38).…”

“…ports in both ApoE-KO and LDL receptor-null mice (24,48,49,53). However, in the earlier studies, the HFD was begun at ϳ1 to ϳ3 mo of age, when growth and bone formation are high (18).…”

Type 1 diabetic bone loss is prevented by novel osteogenic factors

“…There is an inverse relationship between differentiation of mesenchymal stem cells to osteoblasts and adipocytes. Osteoporosis including obesity and diabetes are associated with bone marrow adiposity, which greatly produces tumor necrosis factor-α (TNF-α), an inflammatory cytokine [15][16][17]. TNF-α is found to suppress osteoblastogenesis and mineralization [18,19].…”