TGF-β1 as possible link between loss of bone mineral density and chronic inflammation
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...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
November 22, 2010
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| In: |
PLOS ONE
Year: 2010, Volume: 5, Issue: 11, Pages: 1-9 |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0014073 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1371/journal.pone.0014073 Verlag, lizenzpflichtig, Volltext: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0014073 
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| Author Notes: | Sabrina Ehnert, Johannes Baur, Andreas Schmitt, Markus Neumaier, Martin Lucke, Steven Dooley, Helen Vester, Britt Wildemann, Ulrich Stöckle, Andreas K. Nussler |
MARC
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| 520 | |a 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. | ||
| 650 | 4 | |a Alizarin staining | |
| 650 | 4 | |a Bone resorption | |
| 650 | 4 | |a Cell staining | |
| 650 | 4 | |a Extracellular matrix | |
| 650 | 4 | |a Gene expression | |
| 650 | 4 | |a Osteoblasts | |
| 650 | 4 | |a Osteoclasts | |
| 650 | 4 | |a SMAD signaling | |
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| 700 | 1 | |a Nussler, Andreas K. |e VerfasserIn |4 aut | |
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