title: 1α,25-dihydroxyvitamin D3 and rosiglitazone synergistically enhance osteoblast-mediated mineralization.
abstract: Both vitamin D receptor (VDR) and peroxisome proliferator-activated receptor γ (PPAR-γ) are ligand-activated nuclear transcription factors that are instrumental for bone health. While 1α,25-dihydroxyvitamin D3 (1,25D3), the ligand for VDR, is essential for the development and maintenance of healthy bone, PPAR-γ agonists cause detrimental skeletal effects. Recent studies have revealed evidence for a cross-talk between 1,25D3- and PPAR-α/-δ ligand-mediated signaling but there is a current lack of knowledge regarding cross-talk between signaling of 1,25D3 and the PPAR-γ ligand mediated signaling. In this study, we investigated the cross-talk between 1,25D3- and PPAR-γ agonist rosiglitazone-mediated signaling in human osteoblasts. 1,25D3 slightly but significantly induced expression of the primary PPAR-γ target gene ANGPTL4 but did not influence FABP4. 1,25D3 did not change rosiglitazone regulation of ANGPTL4 and FABP4. The other way around, rosiglitazone reduced CYP24A1 gene expression but this did not change CYP24A1 induction by 1,25D3. The findings regarding CYP24A1 gene expression are in line with the observation that 1,25D3 levels in medium were not affected by rosiglitazone. Furthermore, rosiglitazone significantly inhibited 1,25D3-induction of BGLAP while rosiglitazone alone did not change BGLAP. Additionally, 1,25D3 and rosiglitazone increase osteoblast alkaline phosphatase activity and synergistically stimulated extracellular matrix mineralization. In conclusion, these data provide evidence for a cross-talk between rosiglitazone- and 1,25D3-mediated signaling leading to an acceleration of extracellular matrix mineralization. The data suggest that the reduction of the mineralization inhibitor BGLAP and the increased differentiation status underlie the increased mineralization.
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, 3000CA Rotterdam, The Netherlands.
authors.forename: V J
authors.initials: VJ
authors.lastname: Woeckel
authors.forename: C
authors.initials: C
authors.lastname: Bruedigam
authors.forename: M
authors.initials: M
authors.lastname: Koedam
authors.forename: H
authors.initials: H
authors.lastname: Chiba
authors.forename: B C J
authors.initials: BC
authors.lastname: van der Eerden
authors.forename: J P T M
authors.initials: JP
authors.lastname: van Leeuwen
mesh_terms: D000469:Alkaline Phosphatase / Q000096:biosynthesis; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000378:metabolism; D050071:Bone Density Conservation Agents / Q000819:agonists* / Q000494:pharmacology; D002113:Calcification, Physiologic / Q000187:drug effects*; D002117:Calcitriol / Q000819:agonists* / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004357:Drug Synergism; D005109:Extracellular Matrix / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000819:agonists* / Q000494:pharmacology; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D047493:PPAR alpha / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D048068:PPAR-beta / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D013250:Steroid Hydroxylases / Q000096:biosynthesis; D045162:Thiazolidinediones / Q000819:agonists* / Q000494:pharmacology; D065668:Vitamin D3 24-Hydroxylase
chemical_list: C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D050071:Bone Density Conservation Agents; C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; D007004:Hypoglycemic Agents; D047493:PPAR alpha; D047495:PPAR gamma; D048068:PPAR-beta; D018167:Receptors, Calcitriol; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D000469:Alkaline Phosphatase; D002117:Calcitriol