The Peroxisome Proliferator Activator Receptor Alpha/Delta Agonists Linoleic Acid and Bezafibrate Upregulate Osteoblast Differentiation and Induce Periosteal Bone Formation In Vivo

Abstract

We showed previously that some actions of prostaglandin E(2) (PGE(2)) on bone are caused by its degradation product, PGA(2), which mediates its effects via a class of nuclear receptors known as the peroxisome proliferator activator receptors (PPARs), suggesting that the PPARs may be involved in the regulation of bone formation. The aims of this study were to determine the effects of PPARalpha/delta agonists on bone in vitro and in vivo. PPAR agonists were examined in vitro using the fibroblastic colony-forming unit (CFU-f) assay. The PPARalpha/delta agonists linoleic acid (LA) and bezafibrate (Bez) were then administered to intact male rats by daily s.c. injection for 12 weeks with either vehicle (10% dimethyl sulfoxide), LA (0.3 mg/kg), or Bez (1 mg/kg). CFU-f assays were performed on stromal cells ex vivo. Bone mineral density (BMD) and serum markers of formation and resorption were measured. Bone histomorphometry was performed at cancellous and cortical bone sites. PPARalpha/delta agonists increased significantly the number of osteoblastic colonies as demonstrated by increased alkaline phosphatase activity, collagen production, and calcification. This increase was typically equal to or greater than that achieved with the known bone anabolic agent PGE(2). In intact male rats, LA and Bez increased metaphyseal BMD by 7% and 11%, respectively. Increased BMD was associated with an increase in total bone area, although no changes were observed in bone formation rate within the trabecular compartment. Serum osteocalcin and osteoprogenitor numbers were increased, whereas there was no change in either tartrate-resistant acid phosphatase 5b or osteoclast number. Both LA and Bez increased cortical bone area by approximately 38%, periosteal perimeter by 15%, and periosteal bone formation by 221% and 140%, respectively. There was no effect on medullary cavity area or endocortical perimeter. These data suggest that PPARalpha/delta may have roles in bone anabolism, specifically in the regulation of periosteal bone formation. They are potential therapeutic targets for osteoporosis therapy.

Long-chain polyunsaturated fatty acids: Selected mechanisms of action on bone

“…In addition, the LA peroxidation products 9, 10-epoxyoctadecenoic acid (9,10 EOA), 9,10 dihydroxyoctadecenoic acid (9,10DHOA) and 9-hydroxyoctadecadienoic acid (9-HODE) have also been reported to be ligands for PPARγ2 [144]. Still et al [147] have reported action of LA on bone via binding to PPARα/δ. Due to its binding to fatty acids, the PPAR family can act as sensor of the cellular metabolic state and due to the existence of various PPAR isoforms, cause promoted transcription of enzymes for either fatty acid oxidation (PPARα) or storage (PPARγ) [148].…”

Bezafibrate enhances proliferation and differentiation of osteoblastic MC3T3-E1 cells via AMPK and eNOS activation

“…Fibrate use, including bezafibrate, was associated with a reduced odds of vertebral fractures in men and women [5] . Bezafibrate was shown to increase bone mass in intact male rats principally through increasing periosteal bone formation [6] . A growing body of evidence suggests that bezafibrate plays an important role in bone metabolism.…”

Bezafibrate prevents palmitate-induced apoptosis in osteoblastic MC3T3-E1 cells through the NF-κB signaling pathway

“…Bezafibrate, a dual ligand for peroxisome proliferatoractivated receptors α (PPARα) and PPARδ, is a lipid-lowering drug widely used to treat hypertriglyceridemia (37). Several studies have found that bezafibrate could increase bone mass (16,18). In our experiments, bezafibrate attenuated palmitateinduced apoptosis in MC3T3-E1 cells.…”

“…Moreover, an animal study has shown that lipid lowering by bezafibrate alleviated steroid-induced osteoporosis to the same degrees as statin (17). Another study has found that bezafibrate could increase bone mass in intact male rats principally through increasing periosteal bone formation (18). These results suggest that bezafibrate plays an important role in bone metabolism.…”