ECTS Abstracts (2015) 1 HT2

'Osteocyte-Specific Ablation of Ppar[gamma] Results in Sost Down-Regulation and Increased Periosteal Bone Formation but Decreased Bone Turnover in Mice

Nicolas Bonnet1, Béatrice Desvergne2 & Serge Ferrari1

1Service of Bone Diseases, Faculty of Medicine (UNIGE), University Geneva Hospital (HUG), Geneva, Switzerland; Faculty of Biology and Medicine; 2Center for integrative Genomics, Lausanne, Switzerland.

While heterozygous Pparγ-deficient mice exhibited high bone mass with increased osteoblastogenesis from bone marrow progenitors, the role of Pparγ specifically in late osteoblast/osteocyte (ocy) is not yet properly understood. We crossed Pparγ-loxP with Dmp1-cre mice to generate Ocy-Pparγ−/− and -Pparγ+/+ male mice, which developed normally until 3 months of age, at which time they were analyzed in details. Tissue and cell specificity of Pparγ deletion were confirmed respectively by western blot and immunostaining. Total body lean and fat mass as well as handgrip strength were comparable in Ocy-Pparγ−/− and -Pparγ+/+ mice. Femoral BMD was significantly higher in Ocy-Pparγ−/− (78.6±1.3 vs 73.4±2.1 mg/cm2 in Pparγ+/+, P<0.001). Trabecular and cortical microarchitecture respectively evaluated at the distal and midshaft femur was improved in Ocy-Pparγ−/−: BV/TV +28.6%, TbTh +12.5%, CtTV +9.8%, CtBV +12.0% and CtTh +4.5% compared to Pparγ+/+ (all P<0.05). Periosteal bone forming rate was higher in Ocy-Pparγ-/- (+66.5% vs Pparγ+/+, P<0.05), whereas no significant differences were observed at endocortical surfaces. In contrast CTx was decreased in Ocy-Pparγ−/− (8.6±0.6 vs 12.9±0.5 ng/ml in Pparγ+/+, P<0.001). Gene expression analyses in the osteocytic fraction of cells extracted from the femur showed lower Sost mRNA levels, 50% lower in Ocy-Pparγ−/− compared with Pparγ+/+, whereas Opg or RankL mRNA levels were comparable. However, in the osteoblastic fraction, both Runx2 and Opg levels were significantly higher in Ocy-Pparγ−/−, respectively +19.2% and +197.6% vs Pparγ+/+, both P<0.01. In conclusions, Ocy-specific ablation of Pparγ down-regulates Sost and upregulates Opg expression, resulting in increased periosteal bone formation but lower bone turnover and high bone mass. These observations suggest a role of Pparγ in osteocytes on the control of bone modelling and remodelling by these cells in vivo.

Disclosure: The authors declared no competing interests.

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