Abstract
We showed previously that some actions of prostaglandin E2 (PGE2) on bone are caused by its degradation product, PGA2, 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 PPARα/δ agonists on bone in vitro and in vivo. PPAR agonists were examined in vitro using the fibroblastic colony-forming unit (CFU-f) assay. The PPARα/δ 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. PPARα/δ 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 PGE2. 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 PPARα/δ may have roles in bone anabolism, specifically in the regulation of periosteal bone formation. They are potential therapeutic targets for osteoporosis therapy.
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References
Still K, Scutt A (2001) Stimulation of CFU-f formation by prostaglandin E2 is mediated in part by its degradation product, prostaglandin A2. Prostaglandins Other Lipid Mediat 65:21–31
Devchand PR, Keller H, Peters JM, Vazquez M, Gonzalez FJ, Wahli W (1996) The PPARalpha-leukotriene B4 pathway to inflammation control. Nature 384:39–43
Michalik L, Wahli W (1999) Peroxisome proliferator-activated receptors: three isotypes for a multitude of functions. Curr Opin Biotechnol 10:564–570
Fredenrich A, Grimaldi PA (2005) PPAR delta: an uncompletely known nuclear receptor. Diabetes Metab 31:23–27
Bastie C, Holst D, Gaillard D, Jehl-Pietri C, Grimaldi PA (1999) Expression of peroxisome proliferator–activated receptor PPARdelta promotes induction of PPARgamma and adipocyte differentiation in 3T3C2 fibroblasts. J Biol Chem 274:21920–21925
Kawaguchi H, Akune T, Yamaguchi M, Ohba S, Ogata N, Chung UI, Kubota N, Terauchi Y, Kadowaki T, Nakamura K (2005) Distinct effects of PPARgamma insufficiency on bone marrow cells, osteoblasts, and osteoclastic cells. J Bone Miner Metab 23:275–279
Yu K, Bayona W, Kallen CB, Harding HP, Ravera CP, McMahon G, Brown M, Lazar MA (1995) Differential activation of peroxisome proliferator–activated receptors by eicosanoids. J Biol Chem 270:23975–23983
Forman BM, Chen J, Evans RM (1997) Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator–activated receptors alpha and delta. Proc Natl Acad Sci USA 94:4312–4317
Dobson KR, Reading L, Haberey M, Marine X, Scutt A (1999) Centrifugal isolation of bone marrow from bone: an improved method for the recovery and quantitation of bone marrow osteoprogenitor cells from rat tibiae and femurae. Calcif Tissue Int 65:411–413
Still K, Reading L, Scutt A (2003) Effects of phenol red on CFU-f differentiation and formation. Calcif Tissue Int 73:173–179
Scutt A, Reading L, Scutt N, Still K (2003) Mineralizing fibroblast-colony-forming assays. Methods Mol Med 80:29–39
Ma YF, Ke HZ, Jee WS (1994) Prostaglandin E2 adds bone to a cancellous bone site with a closed growth plate and low bone turnover in ovariectomized rats. Bone 15:137–146
British Medical Journal and Royal Pharmaceutical Society of Great Britain (2005) British National Formulary 50. British Medical Journal Publishing Group and Pharmaceutical Press, London, Chicago
Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR (1987) Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res 2:595–610
Kafienah W, Mistry S, Perry MJ, Politopoulou G, Hollander AP (2007) Pharmacological regulation of adult stem cells: chondrogenesis can be induced using a synthetic inhibitor of the retinoic acid receptor. Stem Cells 25:2460–2468
Jackson SM, Demer LL (2000) Peroxisome proliferator-activated receptor activators modulate the osteoblastic maturation of MC3T3-E1 preosteoblasts. FEBS Lett 471:119–124
Chan BY, Gartland A, Wilson PJ, Buckley KA, Dillon JP, Fraser WD, Gallagher JA (2007) PPAR agonists modulate human osteoclast formation and activity in vitro. Bone 40:149–159
Ke HZ, Jee WS, Mori S, Li XJ, Kimmel DB (1992) Effects of long-term daily administration of prostaglandin-E2 on maintaining elevated proximal tibial metaphyseal cancellous bone mass in male rats. Calcif Tissue Int 50:245–252
Yao W, Jee WS, Zhou H, Lu J, Cui L, Setterberg R, Liang T, Ma Y (1999) Anabolic effect of prostaglandin E2 on cortical bone of aged male rats comes mainly from modeling-dependent bone gain. Bone 25:697–702
Weinreb M, Suponitzky I, Keila S (1997) Systemic administration of an anabolic dose of PGE2 in young rats increases the osteogenic capacity of bone marrow. Bone 20:521–526
Willson TM, Brown PJ, Sternbach DD, Henke BR (2000) The PPARs: from orphan receptors to drug discovery. J Med Chem 43:527–550
Sampath H, Ntambi JM (2005) Polyunsaturated fatty acid regulation of genes of lipid metabolism. Annu Rev Nutr 25:317–340
Rzonca SO, Suva LJ, Gaddy D, Montague DC, Lecka-Czernik B (2004) Bone is a target for the antidiabetic compound rosiglitazone. Endocrinology 145:401–406
Shi Y, Hon M, Evans RM (2002) The peroxisome proliferator–activated receptor delta, an integrator of transcriptional repression and nuclear receptor signaling. Proc Natl Acad Sci USA 99:2613–2618
Lee CH, Chawla A, Urbiztondo N, Liao D, Boisvert WA, Evans RM, Curtiss LK (2003) Transcriptional repression of atherogenic inflammation: modulation by PPARdelta. Science 302:453–457
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This work was supported by grants from Research into Ageing and Strakan Pharmaceuticals.
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Still, K., Grabowski, P., Mackie, I. et al. The Peroxisome Proliferator Activator Receptor Alpha/Delta Agonists Linoleic Acid and Bezafibrate Upregulate Osteoblast Differentiation and Induce Periosteal Bone Formation In Vivo. Calcif Tissue Int 83, 285–292 (2008). https://doi.org/10.1007/s00223-008-9175-9
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DOI: https://doi.org/10.1007/s00223-008-9175-9