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OP0252 Effect of Glucocorticoids and Bisphosphonates on PPAR-Gamma and Hedgehog Pathway in Glucocorticoid-Induced Osteoporosis
  1. T. Xu1,
  2. X. Zhang1
  1. 1Rheumatology, Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangzhou, China

Abstract

Background Previous studies have investigated the molecular mechanisms involved in Glucocorticoid-induced osteoporosis (GIOP), which found that glucocorticoids (GCs) treatment increased bone resorption by prolonging of the lifespan of osteoclasts [1] and decreased bone formation by inhibiting osteoblastogenesis and increasing osteoblast apoptosis [2]. Although it is accepted that reduction of bone formation played a more important part in GIOP [3], the mechanism of how GCs impair the differentiation of osteoblasts is not fully elucidated.

Bisphosphonates (BPs) are approved as the first-line agents by FDA for prevention and treatment of GIOP. The benefits of BPs in GIOP have been ascribed to their anti-resorptive effect, but there is little research focus on their effects in osteogenesis.

Objectives To determine the in vitro and in vivo effect of GCs and BPs on PPARγ and Hedgehog (Hh) pathway in GIOP.

Methods (1) 40 patients with the diagnosis of systemic lupus erythematosus (SLE), of whom 20 had accepted long term (≥6 months) GCs therapy (≥prednisone 5 mg/d) while another 20 were newly diagnosis, were recruited. After baseline bone marrow specimens were collected, 20 newly diagnosis SLE patients were randomly divided into control group (n=10) and alendronate (ALN) treated group (n=10). The second marrow biopsy was performed after 24 weeks therapy. The expression of Gli1 and PPARγ protein of the bone tissues were detected by immunohistochemistry and mean absorbance (A) values were compared between long-term GCs treated group and newly diagnosis group, ALN treated group and control group, respectively. (2) Human bone marrow stem cells (hBMSCs) were co-cultured with hBMSCs growth media. After confluence, cells were committed to differentiate adding adipogenic, rh-SHHN cytokine or osteogenic media with or without increasing concentrations methylprednisone (MP; 10-5 to 10-3mmol/l) or supplemented with low concentration ALN (10-9mol/l). Untreated differentiating hBMSCs were used as control. Oil red O and Alizarin red staining were performed. Finally, levels of expression of PPARγ and Gli1 were measured in mRNA and protein extracts.

Results (1) Compared with newly diagnosis group, the mean A value of Gli1 protein was significantly decreased while that of PPARγ protein was significantly increased in long-term GCs treated group; compared with control group, the mean A value of Gli1 protein was significantly increased while that of PPARγ protein was significantly decreased in ALN treated group. (2) MP affected the differentiation of hBMSCs in a dose-dependent manner. It down-regulated the expression of Gli1 and decreased the number of calcium nodus while up-regulated the expression of PPARγ and increased the number of adipocytes; all these effects could be modified by ALN.

Conclusions This study showed GCs impaired differentiation of osteoblasts through their stimulation effect on the expression of PPARγ and suppression effect on Hh pathway in GIOP; BPs could stimulate osteoblastogenesis and suppress adipogenesis in GIOP.

References

  1. Weinstein RS, et al. Apoptosis and osteoporosis. Am J Med. 2000, 108:153–64

  2. O’Brien CA, et al. Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength. Endocrinology. 2004, 145:1835– 41

  3. Kaneko K, et al. Mechanisms and therapeutics of glucocorticoid-induced osteoporosis. Nihon Rinsho Meneki Gakkai Kaishi. 2011, 34(3): 138-48

Disclosure of Interest None Declared

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