The peroxisome proliferator-activated receptor (PPAR) alpha agonist fenofibrate maintains bone mass, while the PPAR gamma agonist pioglitazone exaggerates bone loss, in ovariectomized rats

Abstract

BackgroundActivation of peroxisome proliferator-activated receptor (PPAR)gamma is associated with bone loss and increased fracture risk, while PPARalpha activation seems to have positive skeletal effects. To further explore these effects we have examined the effect of the PPARalpha agonists fenofibrate and Wyeth 14643, and the PPARgamma agonist pioglitazone, on bone mineral density (BMD), bone architecture and biomechanical strength in ovariectomized rats.MethodsFifty-five female Sprague-Dawley rats were assigned to five groups. One group was sham-operated and given vehicle (methylcellulose), the other groups were ovariectomized and given vehicle, fenofibrate, Wyeth 14643 and pioglitazone, respectively, daily for four months. Whole body and femoral BMD were measured by dual X-ray absorptiometry (DXA), and biomechanical testing of femurs, and micro-computed tomography (microCT) of the femoral shaft and head, were performed.ResultsWhole body and femoral BMD were significantly higher in sham controls and ovariectomized animals given fenofibrate, compared to ovariectomized controls. Ovariectomized rats given Wyeth 14643, maintained whole body BMD at sham levels, while rats on pioglitazone had lower whole body and femoral BMD, impaired bone quality and less mechanical strength compared to sham and ovariectomized controls. In contrast, cortical volume, trabecular bone volume and thickness, and endocortical volume were maintained at sham levels in rats given fenofibrate.ConclusionsThe PPARalpha agonist fenofibrate, and to a lesser extent the PPARaplha agonist Wyeth 14643, maintained BMD and bone architecture at sham levels, while the PPARgamma agonist pioglitazone exaggerated bone loss and negatively affected bone architecture, in ovariectomized rats.

The effect of thiazolidinediones on bone mineral density and bone turnover: systematic review and meta-analysis

“…The majority of fractures in patients taking TZDs in randomised trials occur at cortical sites (humerus, distal forearm, tibia) [4,5], but we did not observe a greater magnitude of bone loss at cortical sites than trabecular sites. Studies in both rodents and humans indicate that TZD exposure is associated with changes in cortical microarchitecture, which will not necessarily be evident on dual-energy x-ray absorptiometry [38][39][40]. Animal studies have also demonstrated that TZD exposure results in increased cortical porosity and decreased cortical thickness in the absence of significant changes in volumetric BMD [38,39].…”

“…Studies in both rodents and humans indicate that TZD exposure is associated with changes in cortical microarchitecture, which will not necessarily be evident on dual-energy x-ray absorptiometry [38][39][40]. Animal studies have also demonstrated that TZD exposure results in increased cortical porosity and decreased cortical thickness in the absence of significant changes in volumetric BMD [38,39]. In women using TZDs, reduction in polar strength strain index at highly cortical sites has been observed [40].…”

MK886 inhibits the pioglitazone-induced anti-invasion of MDA-MB-231 cells is associated with PPARα/γ, FGF4 and 5LOX

“…ALPI activity has been reported to increase following the administration of a PPARa agonist (Stunes et al 2011). However, high levels of ALPI expression were observed in both PGZ-treated and MK886-treated MDA-MB-231 cells throughout the experiments.…”

An energetic orphan in an endocrine tissue: A revised perspective of the function of estrogen receptor-related receptor alpha in bone and cartilage

“…In this article we do not review these in detail, but they include: (1) small heterodimer partner (SHP), which physically interacts with all three ERRs, repressing their activity (27)(28)(29) ; (2) hypoxia-inducible factor-a (HIF1a), which physically interacts with ERRa to stimulate HIF-induced transcription (30)(31)(32)(33) ; and (3) vascular endothelial growth factor (VEGF), which is a direct target gene of the ERRa/PGC1a complex and HIF1a in muscle and in breast cancer cells. (34,35) Several factors, including prostaglandin E1, BMP, and insulin-like growth factor 1, known to regulate ERRa or g expression and/or activity, also modulate VEGF production in bone cells, suggesting direct VEGF regulation by ERRa/g in OBs and OCs (10,25,38,39) ; (4) aryl hydrocarbon receptor (AhR), which has been reported to interact with ERa and ERRa (40)(41)(42)(43) ; (5) PPARa, which was reported to be directly regulated by ERRa in cardiac myocytes and skeletal muscles (44)(45)(46) ; and (6) Wnt11, which has been shown to be regulated in breast cancer cells by ERRa/b-catenin complex and in C3H10T1/2 cells through its interaction with PGC1a. (12,(47)(48)(49) Recently, we found osteoprotegerin (OPG) regulated in breast cancer cells impacting on bone metastases formation.…”