Parathyroid hormone (PTH) is a key regulator of bone metabolism and is used as anabolic pharmacotherapy for treatment of osteoporosis. Recent evidence suggests that lipids may affect bone metabolism and that intermittent PTH therapy may fail in the presence of hyperlipidemia. This is clinically important because hyperlipidemia is prevalent in patients with osteoporosis even accounting for age. In the hyperlipidemic condition, bioactive derivatives of low-density lipoproteins (LDL) are generated in the subendothelial space of tissues, triggering chronic inflammatory responses including oxidant stress and expression of cytokines and chemokines. We have found that these inflammatory lipoproteins/lipids are also present in bone and that they inhibit osteoblastic differentiation. In additional studies, we and other investigators demonstrated that hyperlipidemic mice have reduced bone density compared to WT mice. Our preliminary studies, both in vitro and in vivo, now show that lipids inhibit PTH-induced immediate early genes, including Nurr1, a transcriptional regulator of osteoblastic genes, by attenuating cyclic AMP production and that hyperlipidemia blunts PTH-induced osteoanabolism in vivo, primarily in cortical bone. These findings strongly suggest that hyperlipidemia induces PTH resistance. Whether PTH resistance is at the molecular and/or tissue level remains to be determined. Since osteoporosis and hyperlipidemia remain widespread despite treatment, understanding effects of lipids on basal (endogenous) and intermittent (exogenous) PTH may provide new approaches to osteoporosis. We hypothesize that inflammatory lipoproteins, which are increased in hyperlipidemia, reduce PTH anabolic effects. Based on our preliminary studies, in Specific Aim 1, we will test in vitro whether the inhibitory mechanism of lipids on PTH-induced cyclic AMP production is at the level of PTH receptor expression, receptor trafficking, downstream at the level of G-protein activation, or further downstream at the level of adenylate cyclase activation.
In Specific Aim 2, we will identify the level at which lipid-induced PTH resistance occurs in vivo: at the level of differentiation of marrow progenitors toward osteogenic vs. adipogenic lineages;anabolic responses of mature osteoblasts/osteocytes;and/or transient expression of osteoclastogenic factors by osteoblasts. We will generate Ldlr-/- mice that express green fluorescent protein targeted to osteoblasts and osteocytes.
In Specific Aim 3, we will test whether reducing hyperlipidemia or inhibiting lipid oxidation will reverse PTH resistance in vivo by measuring bone density, histomorphometric parameters and bone turnover markers in the hyperlipidemic (Ldlr-/-) mice that are treated with liver X receptor agonists or that overexpress the anti-oxidant enzyme, paraoxonase-1. These proposed studies will provide insights into how inflammatory lipids inhibit PTH-induced osteoanabolism, pinpoint the site of inhibitory action within the PTH signaling pathway, and demonstrate approaches to reverse lipid-induced PTH dysregulation.
Relevance to Public Health High cholesterol is common in patients with the low bone density disease, osteoporosis. Parathyroid hormone treatment is a promising therapy for osteoporosis, but evidence suggests that it may be much less effective in patients with high cholesterol. The proposed studies will determine how unmanaged cholesterol level reduces efficacy of the treatment so that corrective strategies can be developed.
| Demer, Linda L; Tintut, Yin; Nguyen, Kim-Lien et al. (2017) Rigor and Reproducibility in Analysis of Vascular Calcification. Circ Res 120:1240-1242 |
| Lim, Jina; Ehsanipour, Arshia; Hsu, Jeffrey J et al. (2016) Inflammation Drives Retraction, Stiffening, and Nodule Formation via Cytoskeletal Machinery in a Three-Dimensional Culture Model of Aortic Stenosis. Am J Pathol 186:2378-89 |
| Li, Xin; Lim, Jina; Lu, Jinxiu et al. (2015) Protective Role of Smad6 in Inflammation-Induced Valvular Cell Calcification. J Cell Biochem 116:2354-64 |
| Demer, Linda L; Boström, Kristina I (2015) Conflicting forces of warfarin and matrix gla protein in the artery wall. Arterioscler Thromb Vasc Biol 35:9-10 |
| Demer, Linda L; Tintut, Yin (2015) The leading edge of vascular calcification. Trends Cardiovasc Med 25:275-7 |
| Keuroghlian, Armand; Barroso, Ana Dilza Viana; Kirikian, Gary et al. (2015) The effects of hyperlipidemia on implant osseointegration in the mouse femur. J Oral Implantol 41:e7-e11 |
| Tintut, Yin; Demer, Linda L (2015) Exosomes: nanosized cellular messages. Circ Res 116:1281-3 |
| Ascenzi, Maria-Grazia; Lutz, Andre; Du, Xia et al. (2014) Hyperlipidemia affects multiscale structure and strength of murine femur. J Biomech 47:2436-43 |
| Demer, Linda L; Tintut, Yin (2014) Inflammatory, metabolic, and genetic mechanisms of vascular calcification. Arterioscler Thromb Vasc Biol 34:715-23 |
| van Venrooij, Natalie A; Pereira, Renata C; Tintut, Yin et al. (2014) FGF23 protein expression in coronary arteries is associated with impaired kidney function. Nephrol Dial Transplant 29:1525-32 |
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