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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK081346-04
Application #
8248315
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Malozowski, Saul N
Project Start
2009-05-08
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$328,285
Indirect Cost
$115,113
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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
Li, Xin; Garcia, Jamie; Lu, Jinxiu et al. (2014) Roles of parathyroid hormone (PTH) receptor and reactive oxygen species in hyperlipidemia-induced PTH resistance in preosteoblasts. J Cell Biochem 115:179-88
Tintut, Yin; Demer, Linda L (2014) Effects of bioactive lipids and lipoproteins on bone. Trends Endocrinol Metab 25:53-9
Lu, Jinxiu; Cheng, Henry; Atti, Elisa et al. (2013) Role of paraoxonase-1 in bone anabolic effects of parathyroid hormone in hyperlipidemic mice. Biochem Biophys Res Commun 431:19-24
Sallam, Tamer; Cheng, Henry; Demer, Linda L et al. (2013) Regulatory circuits controlling vascular cell calcification. Cell Mol Life Sci 70:3187-97
Chen, Ting-Hsuan; Hsu, Jeffrey J; Zhao, Xin et al. (2012) Left-right symmetry breaking in tissue morphogenesis via cytoskeletal mechanics. Circ Res 110:551-9
Li, Rongsong; Mittelstein, David; Lee, Juhyun et al. (2012) A dynamic model of calcific nodule destabilization in response to monocyte- and oxidized lipid-induced matrix metalloproteinases. Am J Physiol Cell Physiol 302:C658-65
Pirih, Flavia; Lu, Jinxiu; Ye, Fei et al. (2012) Adverse effects of hyperlipidemia on bone regeneration and strength. J Bone Miner Res 27:309-18
Sage, Andrew P; Lu, Jinxiu; Tintut, Yin et al. (2011) Hyperphosphatemia-induced nanocrystals upregulate the expression of bone morphogenetic protein-2 and osteopontin genes in mouse smooth muscle cells in vitro. Kidney Int 79:414-22

Showing the most recent 10 out of 23 publications