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BMC Musculoskeletal Disorders
Published in: BMC Musculoskeletal Disorders 1/2019

Open Access 01-12-2019 | Knee Osteoarthritis | Research article

Transforming growth factor-β stimulates nerve growth factor production in osteoarthritic synovium

Authors: Shotaro Takano, Kentaro Uchida, Makoto Itakura, Dai Iwase, Jun Aikawa, Gen Inoue, Manabu Mukai, Masayuki Miyagi, Kosuke Murata, Hiroyuki Sekiguchi, Masashi Takaso

Published in: BMC Musculoskeletal Disorders | Issue 1/2019

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Abstract

Background

Nerve growth factor (NGF) contributes to pain in knee osteoarthritis (KOA) patients. Transforming growth factor-beta (TGF-β) stimulates NGF expression in chondrocytes from KOA patients. However, the correlation between synovial TGF-β and NGF levels has not been sufficiently studied in human KOA patients. Further, the mechanism governing NGF regulation by TGF-β in synovial cells is unclear.

Methods

During total knee arthroplasty, we extracted the synovial tissue (SYT) of 107 subjects with unilateral Kellgren/Lawrence grade 3–4 KOA confirmed by radiography. We examined the distribution of TGF-β and NGF using immunohistochemistry, and analyzed the relationship between NGF and TGFB mRNA levels. Cultured synovial cells extracted from SYT were exposed to culture medium (control), human recombinant TGF-β (rhTGF-β), rhTGF-β + ALK5 inhibitor SB505124, rhTGF-β + transforming growth factor activating kinase 1 (TAK1) inhibitor (5Z)-7-oxozeaenol, or rhTGF-β + p38 inhibitor SB203580 for 30 min, 6 h and 24 h. NGF mRNA expressed by the cultured cells and NGF protein levels in the cell supernatant were detected by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Phosphorylation of p38 was evaluated by western blotting.

Results

NGF mRNA levels were positively correlated with those of TGFB. Cells expressing TGF-β and NGF protein were observed in the lining layer of SYT. TGF-β stimulated increased NGF mRNA expression and NGF protein production. The ALK5 inhibitor completely suppressed the TGF-β-mediated increase in NGF expression and NGF production in synovial cells. ALK5, TAK1 and p38 inhibitors inhibited the TGF-β-induced phosphorylation of p38, and TAK1 and p38 inhibitors partially inhibited the TGF-β-mediated increase in NGF expression and NGF production in synovial cells.

Conclusion

TGF-β regulates NGF production via the TGF-β/ALK5 signaling pathway in osteoarthritic synovium. This effect may partially occur through inhibition of the TAK1/p38 pathway in the SYT of KOA patients.
Appendix
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Metadata
Title
Transforming growth factor-β stimulates nerve growth factor production in osteoarthritic synovium
Authors
Shotaro Takano
Kentaro Uchida
Makoto Itakura
Dai Iwase
Jun Aikawa
Gen Inoue
Manabu Mukai
Masayuki Miyagi
Kosuke Murata
Hiroyuki Sekiguchi
Masashi Takaso
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Musculoskeletal Disorders / Issue 1/2019
Electronic ISSN: 1471-2474
DOI
https://doi.org/10.1186/s12891-019-2595-z

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