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Transforming growth factor-? stimulates nerve growth factor production in osteoarthritic synovium.

ABSTRACT: BACKGROUND:Nerve growth factor (NGF) contributes to pain in knee osteoarthritis (KOA) patients. Transforming growth factor-beta (TGF-?) stimulates NGF expression in chondrocytes from KOA patients. However, the correlation between synovial TGF-? and NGF levels has not been sufficiently studied in human KOA patients. Further, the mechanism governing NGF regulation by TGF-? 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-? 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-? (rhTGF-?), rhTGF-??+?ALK5 inhibitor SB505124, rhTGF-??+?transforming growth factor activating kinase 1 (TAK1) inhibitor (5Z)-7-oxozeaenol, or rhTGF-??+?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-? and NGF protein were observed in the lining layer of SYT. TGF-? stimulated increased NGF mRNA expression and NGF protein production. The ALK5 inhibitor completely suppressed the TGF-?-mediated increase in NGF expression and NGF production in synovial cells. ALK5, TAK1 and p38 inhibitors inhibited the TGF-?-induced phosphorylation of p38, and TAK1 and p38 inhibitors partially inhibited the TGF-?-mediated increase in NGF expression and NGF production in synovial cells. CONCLUSION:TGF-? regulates NGF production via the TGF-?/ALK5 signaling pathway in osteoarthritic synovium. This effect may partially occur through inhibition of the TAK1/p38 pathway in the SYT of KOA patients.

SUBMITTER: Takano S

PROVIDER: S-EPMC6511148 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Takano Shotaro S Uchida Kentaro K Itakura Makoto M Iwase Dai D Aikawa Jun J Inoue Gen G Mukai Manabu M Miyagi Masayuki M Murata Kosuke K Sekiguchi Hiroyuki H Takaso Masashi M

BMC musculoskeletal disorders 20190510 1

<h4>Background</h4>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.<h4>Methods</h4>During total knee arthroplasty, we extracted the synovial tissue (SYT) of ...[more]

PMID: 31077183

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Project description:BackgroundChronic fatigue syndrome (CFS) is a prevalent and disabling condition among adolescent. The disease mechanisms are unknown. Previous studies have suggested elevated plasma levels of several cytokines, but a recent meta-analysis of 38 articles found that of 77 different cytokines measured in plasma, transforming growth factor beta (TGF-β) was the only one that was elevated in patients compared to controls in a sufficient number of articles. In the present study we therefore compared the plasma levels of the three TGF-β isoforms in adolescent CFS patients and healthy controls. In addition, the study explored associations between TGF-β levels, neuroendocrine markers, clinical markers and differentially expressed genes within the CFS group.MethodsCFS patients aged 12-18 years (n = 120) were recruited nation-wide to a single referral center as part of the NorCAPITAL project (ClinicalTrials ID: NCT01040429). A broad case definition of CFS was applied, requiring 3 months of unexplained, disabling chronic/relapsing fatigue of new onset, whereas no accompanying symptoms were necessary. Healthy controls (n = 68) were recruited from local schools. The three isoforms of TGF-β (TGF-β1, TGF-β2, TGF-β3) were assayed using multiplex technology. Neuroendocrine markers encompassed plasma and urine levels of catecholamines and cortisol, as well as heart rate variability indices. Clinical markers consisted of questionnaire scores for symptoms of post-exertional malaise, inflammation, fatigue, depression and trait anxiety, as well as activity recordings. Whole blood gene expression was assessed by RNA sequencing in a subgroup of patients (n = 29) and controls (n = 18).ResultsPlasma levels of all three isoforms of TGF-β were equal in the CFS patients and the healthy controls. Subgrouping according to the Fukuda and Canada 2003 criteria of CFS did not reveal differential results. Within the CFS group, all isoforms of TGF-β were associated with plasma cortisol, urine norepinephrine and urine epinephrine, and this association pattern was related to fatigue score. Also, TGF-β3 was related to expression of the B cell annotated genes TNFRSF13C and CXCR5.ConclusionsPlasma levels of all TGF-β isoforms were not altered in adolescent CFS. However, the TGF-β isoforms were associated with neuroendocrine markers, an association related to fatigue score. Furthermore, TGF-β3 might partly mediate an association between plasma cortisol and B cell gene expression. Trial registration Clinical Trials NCT01040429.

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Transforming growth factor-? stimulates nerve growth factor production in osteoarthritic synovium.

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

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