TGF-β1 as possible link between loss of bone mineral density and chronic inflammation

• Verfasst von: Ehnert, Sabrina [VerfasserIn]
• Verfasst von: Baur, Johannes [VerfasserIn]
• Verfasst von: Schmitt, Andreas [VerfasserIn]
• Verfasst von: Neumaier, Markus [VerfasserIn]
• Verfasst von: Lucke, Martin [VerfasserIn]
• Verfasst von: Dooley, Steven [VerfasserIn]
• Verfasst von: Vester, Helen [VerfasserIn]
• Verfasst von: Wildemann, Britt [VerfasserIn]
• Verfasst von: Stöckle, Ulrich [VerfasserIn]
• Verfasst von: Nussler, Andreas K. [VerfasserIn]
• Titel: TGF-β1 as possible link between loss of bone mineral density and chronic inflammation
• Verf.angabe: Sabrina Ehnert, Johannes Baur, Andreas Schmitt, Markus Neumaier, Martin Lucke, Steven Dooley, Helen Vester, Britt Wildemann, Ulrich Stöckle, Andreas K. Nussler
• E-Jahr: 2010
• Jahr: November 22, 2010
• Umfang: 9 S.
• Fussnoten: Gesehen am 22.05.2023 ; Im Titel ist die Ziffer 1 bei TGF-β1 tiefgestellt
• Titel Quelle: Enthalten in: PLOS ONE
• Ort Quelle: San Francisco, California, US : PLOS, 2006
• Jahr Quelle: 2010
• Band/Heft Quelle: 5(2010), 11 vom: Nov., Artikel-ID e14073, Seite 1-9
• ISSN Quelle: 1932-6203
• DOI: doi:10.1371/journal.pone.0014073
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Alizarin staining
• Sach-SW: Bone resorption
• Sach-SW: Cell staining
• Sach-SW: Extracellular matrix
• Sach-SW: Gene expression
• Sach-SW: Osteoblasts
• Sach-SW: Osteoclasts
• Sach-SW: SMAD signaling
• K10plus-PPN: 1845889665

Abstract

Background The TGF family plays a key role in bone homeostasis. Systemic or topic application of proteins of this family apparently positively affects bone healing in vivo. However, patients with chronic inflammation, having increased TGF-β1 serum-levels, often show reduced bone mineral content and disturbed bone healing. Therefore, we wanted to identify intracellular mechanisms induced by chronic presence of TGF-β1 and their possible role in bone homeostasis in primary human osteoblasts. Methodology/Principal Findings Osteoblasts were isolated from femur heads of patients undergoing total hip replacement. Adenoviral reporter assays showed that in primary human osteoblasts TGF-β1 mediates its signal via Smad2/3 and not Smad1/5/8. It induces proliferation as an intermediate response but decreases AP-activity and inorganic matrix production as a late response. In addition, expression levels of osteoblastic markers were strongly regulated (AP↓; Osteocalcin↓; Osteopontin↑; MGP↓; BMP 2↓; BSP2↓; OSF2↓; Osteoprotegerin↓; RANKL↑) towards an osteoclast recruiting phenotype. All effects were blocked by inhibition of Smad2/3 signaling with the Alk5-Inhibitor (SB431542). Interestingly, a rescue experiment showed that reduced AP-activities did not recover to base line levels, even 8 days after stopping the TGF-β1 application. Conclusions/Significance In spite of the initial positive effects on cell proliferation, it is questionable if continuous Smad2/3 phosphorylation is beneficial for bone healing, because decreased AP-activity and BMP2 levels indicate a loss of function of the osteoblasts. Thus, inhibition of Smad2/3 phosphorylation might positively influence functional activity of osteoblasts in patients with chronically elevated TGF-β1 levels and thus, could lead to an improved bone healing in vivo.