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?

Davidson, E.N. Blaney; Caam, A. van; Vitters, E.L.; Bennink, Miranda B.; Thijssen, Eva; Berg, Wim B. van den; Koenders, Marije I.; Lent, P.L.E.M. van; Loo, Fons A. J. van de; Kraan, P.M. van der

doi:10.1016/j.joca.2014.12.005

Cited by 69 publications

(67 citation statements)

References 32 publications

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“…However, TGF-β signaling can play both protective and deleterious roles in OA, explained in part by the alteration of signaling pathways in aging chondrocytes through decreased ALK5, the canonical receptor that activates Smad2/3 to inhibit chondrocyte hypertrophy, and increased ALK1, which signals through Smad1/5/8 to induce MMP-13 and cartilage catabolism [125] and NGF [126]. Disruption of the pericellular matrix by the TGF-β-induced serine proteinase, HTRA1, may be one of the earliest events in OA chondrocyte activation [28].…”

Section: Cartilage Anabolism and Tissue Engineering Strategiesmentioning

confidence: 99%

Emerging targets in osteoarthritis therapy

Goldring

Bérenbaum

2015

Current Opinion in Pharmacology

147

124

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Osteoarthritis (OA) is a destructive joint disease in which the initiation may be attributed to direct injury and mechanical disruption of joint tissues, but the progressive changes are dependent on active cell-mediated processes that can be observed or inferred during the generally long time-course of the disease. Based on clinical observations and experimental studies, it is now recognized a that it is possible for individual patients to exhibit common sets of symptoms and structural abnormalities due to distinct pathophysiological pathways that act independently or in combination. Recent research that has focused on the underlying mechanisms involving biochemical cross talk among the cartilage, synovium, bone, and other joint tissues within a background of poorly characterized genetic factors will be addressed in this review.

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Section: Cartilage Anabolism and Tissue Engineering Strategiesmentioning

confidence: 99%

Emerging targets in osteoarthritis therapy

Goldring

Bérenbaum

2015

Current Opinion in Pharmacology

147

124

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“…Хотя, по данным некоторых исследований на хондроцитах животных и человека in vitro [34], ТРФβ1 мо-жет участвовать в активации ФРН и усиливать боль, дру-гие исследования, напротив, связывают повышенную экспрессию ТРФβ1 с подавлением боли, ассоциирован-ным с усилением процессов регенерации ткани [35][36][37][38]. При этом отмечалась отрицательная корреляция между уровнями ТРФβ1 и рентгенологической стадией ОА [56].…”

Section: Discussionunclassified

“…Кроме того, недавно показано, что активация ФРН, который, как известно, участвует в развитии болевых ощу-щений при ОА, может индуцироваться трансформирую-щим ростовым фактором β1 (ТРФβ1) посредством ALK5-Smad2/3 сигнального пути [34]. В этом случае боль может быть связана с разрушением матрикса суставного хряща и высвобождением локализованного в матриксе TРФβ1.…”

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Molecular mechanisms of pain regulation in patients with osteoarthritis

Chetina¹,

Маркова²,

Taskina³

et al. 2016

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“…In particular, TGF-β1 promotes NGF expression in chondrocytes in a Smad2/3-dependent manner (22). By contrast, TGF-β relays its intracellular signaling through non-Smad signaling pathways, such as c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) signaling (23).…”

Section: Introductionmentioning

confidence: 99%

IL‑1β and TNF‑α suppress TGF‑β‑promoted NGF expression in periodontal ligament‑derived fibroblasts through inactivation of TGF‑β‑induced Smad2/3‑ and p38 MAPK‑mediated signals

et al. 2018

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Mechanosensitive (MS) neurons in the periodontal ligament (PDL) pass information to the trigeminal ganglion when excited by mechanical stimulation of the tooth. During occlusal tooth trauma of PDL tissues, MS neurons are injured, resulting in atrophic neurites and eventual degeneration of MS neurons. Nerve growth factor (NGF), a neurotrophic factor, serves important roles in the regeneration of injured sensory neurons. In the present study, the effect of pro‑inflammatory cytokines, including interleukin 1β (IL‑1β) and tumor necrosis factor α (TNF‑α), on transforming growth factor β1 (TGF‑β1)‑induced NGF expression was evaluated in rat PDL‑derived SCDC2 cells. It was observed that TGF‑β1 promoted NGF expression via Smad2/3 and p38 mitogen‑activated protein kinase (MAPK) activation. IL‑1β and TNF‑α suppressed the TGF‑β1‑induced activation of Smad2/3 and p38 MAPK, resulting in the abrogation of NGF expression. NGF secreted by TGF‑β1‑treated SCDC2 cells promoted neurite extension and the expression of tyrosine hydroxylase, a rate‑limiting enzyme in dopamine synthesis in rat pheochromocytoma PC12 cells. These results suggested that pro‑inflammatory cytokines suppressed the TGF‑β‑mediated expression of NGF in PDL‑derived fibroblasts through the inactivation of TGF‑β‑induced Smad2/3 and p38 MAPK signaling, possibly resulting in the disturbance of the regeneration of injured PDL neurons.

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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?

Abstract: We show for the first time that TGF-β induces NGF expression in chondrocytes, in a ALK5-Smad2/3 dependent manner. This reveals a potential alternative non-inflammatory source of pain in OA.

Cited by 69 publications

References 32 publications

Emerging targets in osteoarthritis therapy

Emerging targets in osteoarthritis therapy

Molecular mechanisms of pain regulation in patients with osteoarthritis

IL‑1β and TNF‑α suppress TGF‑β‑promoted NGF expression in periodontal ligament‑derived fibroblasts through inactivation of TGF‑β‑induced Smad2/3‑ and p38 MAPK‑mediated signals

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