TGF-β is a potent inducer of Nerve Growth Factor in articular cartilage via the ALK5-Smad2/3 pathway. Potential role in OA related pain?

被引：66

作者：

Davidson, E. N. Blaney ^{[1
]}

van Caam, A. P. M. ^{[1
]}

Vitters, E. L. ^{[1
]}

Bennink, M. B. ^{[1
]}

Thijssen, E. ^{[1
]}

van den Berg, W. B. ^{[1
]}

Koenders, M. I. ^{[1
]}

van Lent, P. L. E. M. ^{[1
]}

van de Loo, F. A. J. ^{[1
]}

van der Kraan, P. M. ^{[1
]}

机构：

[1] Radboud Univ Nijmegen, Med Ctr, NL-6500 HB Nijmegen, Netherlands

来源：

OSTEOARTHRITIS AND CARTILAGE | 2015年 / 23卷 / 03期

关键词：

Pain; Cartilage; TGF-beta; NGF; Smad; PHASE-III TRIAL; DOUBLE-BLIND; OSTEOARTHRITIS PAIN; FACTOR EXPRESSION; FACTOR NGF; TANEZUMAB; KNEE; RELEASE; CHONDROCYTES; HIP;

D O I：

10.1016/j.joca.2014.12.005

中图分类号：

R826.8 [整形外科学]; R782.2 [口腔颌面部整形外科学]; R726.2 [小儿整形外科学]; R62 [整形外科学（修复外科学）];

学科分类号：

100224 [整形外科学];

摘要：

Objective: Pain is the main problem for patients with osteoarthritis (OA). Pain is linked to inflammation, but in OA a subset of patients suffers from pain without inflammation, indicating an alternative source of pain. Nerve Growth Factor (NGF) inhibition is very efficient in blocking pain during OA, but the source of NGF is unclear. We hypothesize that damaged cartilage in OA releases Transforming Growth Factor-beta (TGF-beta), which in turn stimulates chondrocytes to produce NGF. Design: Murine and human chondrocyte cell lines, primary bovine and human chondrocytes, and cartilage explants from bovine metacarpal joints and human OA joints were stimulated with TGF-beta 1 and/or Interleukin-1 (IL-1)beta. We analyzed NGF expression on mRNA level with QPCR and stained human OA cartilage for NGF immunohistochemically. Cultures were additionally pre-incubated with inhibitors for TAK1, Smad2/3 or Smad1/5/8 signaling to identify the TGF-beta pathway inducing NGF. Results: NGF expression was consistently induced in higher levels by TGF-beta than IL-1 in all of our experiments: murine, bovine and human origin, in cell lines, primary chondrocytes and explants cultures. TAK1 inhibition consistently reduced TGF-beta-induced NGF whereas it fully blocked IL-1 beta-induced NGF expression. In contrast, ALK5-Smad2/3 inhibition fully blocked TGF-beta-induced NGF expression. Despite the large variation in basal NGF in human OA samples (mRNA and histology), TGF-beta exposure led to a consistent high level of NGF induction. Conclusion: We show for the first time that TGF-beta induces NGF expression in chondrocytes, in a ALK5-Smad2/3 dependent manner. This reveals a potential alternative non-inflammatory source of pain in OA. (C) 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

引用

页码：478 / 486

页数：9

共 34 条

[1]

Efficacy and safety of tanezumab added on to diclofenac sustained release in patients with knee or hip osteoarthritis: a double-blind, placebo-controlled, parallel-group, multicentre phase III randomised clinical trial [J].

Balanescu, Andra Rodica ;

Feist, Eugen ;

Wolfram, Gernot ;

Davignon, Isabelle ;

Smith, Michael D. ;

Brown, Mark T. ;

West, Christine R. .

ANNALS OF THE RHEUMATIC DISEASES, 2014, 73 (09) :1665-1672

[2]

Targeting Nerve Growth Factor (NGF) for Pain Management: What Does the Future Hold for NGF Antagonists? [J].

Bannwarth, Bernard ;

Kostine, Marie .

DRUGS, 2014, 74 (06) :619-626

[3]

TGF-β Signaling Protects Retinal Neurons from Programmed Cell Death during the Development of the Mammalian Eye [J].

Braunger, Barbara M. ;

Pielmeier, Stefan ;

Demmer, Cora ;

Landstorfer, Victoria ;

Kawall, Daniela ;

Abramov, Natalie ;

Leibinger, Marco ;

Kleiter, Ingo ;

Fischer, Dietmar ;

Jaegle, Herbert ;

Tamm, Ernst R. .

JOURNAL OF NEUROSCIENCE, 2013, 33 (35) :14246-14258

[4]

Tanezumab Reduces Osteoarthritic Hip Pain Results of a Randomized, Double-Blind, Placebo-Controlled Phase III Trial [J].

Brown, Mark T. ;

Murphy, Frederick T. ;

Radin, David M. ;

Davignon, Isabelle ;

Smith, Michael D. ;

West, Christine R. .

ARTHRITIS AND RHEUMATISM, 2013, 65 (07) :1795-1803

[5]

Tanezumab Reduces Osteoarthritic Knee Pain: Results of a Randomized, Double-Blind, Placebo-Controlled Phase III Trial [J].

Brown, Mark T. ;

Murphy, Frederick T. ;

Radin, David M. ;

Davignon, Isabelle ;

Smith, Michael D. ;

West, Christine R. .

JOURNAL OF PAIN, 2012, 13 (08) :790-798

[6]

SB-505124 is a selective inhibitor of transforming growth factor-β type I receptors ALK4, ALK5, and ALK7 [J].

Byfield, SD ;

Major, C ;

Laping, NJ ;

Roberts, AB .

MOLECULAR PHARMACOLOGY, 2004, 65 (03) :744-752

[7]

Structure-activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors [J].

Cuny, Gregory D. ;

Yu, Paul B. ;

Laha, Joydev K. ;

Xing, Xuechao ;

Liu, Ji-Feng ;

Lai, Carol S. ;

Deng, Donna Y. ;

Sachidanandan, Chetana ;

Bloch, Kenneth D. ;

Peterson, Randall T. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (15) :4388-4392

[8]

TGF β-induced cartilage repair is maintained but fibrosis is blocked in the presence of Smad7 [J].

Davidson, Esmeralda N. Blaney ;

Vitters, Elly L. ;

van den Berg, Wim B. ;

van der Kraan, Peter M. .

ARTHRITIS RESEARCH & THERAPY, 2006, 8 (03)

[9]

Increase in ALK1/ALK5 Ratio as a Cause for Elevated MMP-13 Expression in Osteoarthritis in Humans and Mice [J].

Davidson, Esmeralda N. Blaney ;

Remst, Dennis F. G. ;

Vitters, Elly L. ;

van Beuningen, Henk M. ;

Blom, Arjen B. ;

Goumans, Marie-Jose ;

van den Berg, Wim B. ;

van der Kraan, Peter M. .

JOURNAL OF IMMUNOLOGY, 2009, 182 (12) :7937-7945

[10]

Pain - Understanding and challenges for the rheumatologist [J].

Fitzcharles, MA ;

Almahrezi, A ;

Shir, Y .

ARTHRITIS AND RHEUMATISM, 2005, 52 (12) :3685-3692

← 1 2 3 4 →