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Citations to this article

Distinct roles of Smad pathways and p38 pathways in cartilage-specific gene expression in synovial fibroblasts
Hiroaki Seto, … , Hiroshi Kawaguchi, Sakae Tanaka
Hiroaki Seto, … , Hiroshi Kawaguchi, Sakae Tanaka
Published March 1, 2004
Citation Information: J Clin Invest. 2004;113(5):718-726. https://doi.org/10.1172/JCI19899.
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Article Bone biology

Distinct roles of Smad pathways and p38 pathways in cartilage-specific gene expression in synovial fibroblasts

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Abstract

The role of TGF-β/bone morphogenetic protein signaling in the chondrogenic differentiation of human synovial fibroblasts (SFs) was examined with the adenovirus vector–mediated gene transduction system. Expression of constitutively active activin receptor–like kinase 3 (ALK3CA) induced chondrocyte-specific gene expression in SFs cultured in pellets or in SF pellets transplanted into nude mice, in which both the Smad and p38 pathways are essential. To analyze downstream cascades of ALK3 signaling, we utilized adenovirus vectors carrying either Smad1 to stimulate Smad pathways or constitutively active MKK6 (MKK6CA) to activate p38 pathways. Smad1 expression had a synergistic effect on ALK3CA, while activation of p38 MAP kinase pathways alone by transduction of MKK6CA accelerated terminal chondrocytic differentiation, leading to type X collagen expression and enhanced mineralization. Overexpression of Smad1 prevented MKK6CA-induced type X collagen expression and maintained type II collagen expression. In a mouse model of osteoarthritis, activated p38 expression as well as type X collagen staining was detected in osteochondrophytes and marginal synovial cells. These results suggest that SFs can be differentiated into chondrocytes via ALK3 activation and that stimulating Smad pathways and controlling p38 activation at the proper level can be a good therapeutic strategy for maintaining the healthy joint homeostasis and treating degenerative joint disorders.

Authors

Hiroaki Seto, Satoshi Kamekura, Toshiki Miura, Aiichiro Yamamoto, Hirotaka Chikuda, Toru Ogata, Hisatada Hiraoka, Hiromi Oda, Kozo Nakamura, Hisashi Kurosawa, Ung-il Chug, Hiroshi Kawaguchi, Sakae Tanaka

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Total citations by year

Year: 2022 2019 2016 2014 2012 2011 2010 2008 Total
Citations: 1 1 2 2 1 1 1 1 10
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Citations to this article (10)

Title and authors Publication Year
Intervertebral disc degeneration is rescued by TGFβ/BMP signaling modulation in an ex vivo filamin B mouse model
J Zieba, K Forlenza, K Heard, J Martin, M Bosakova, D Cohn, S Robertson, P Krejci, D Krakow
Bone Research 2022
Novel Hybrid Gels Made of High and Low Molecular Weight Hyaluronic Acid Induce Proliferation and Reduce Inflammation in an Osteoarthritis In Vitro Model Based on Human Synoviocytes and Chondrocytes
A Stellavato, V Vassallo, AL Gatta, AV Pirozzi, MD Rosa, G Balato, A DAddona, V Tirino, C Ruosi, C Schiraldi
BioMed Research International 2019
PPAR-α Agonist WY-14643 Inhibits LPS-Induced Inflammation in Synovial Fibroblasts via NF-kB Pathway
D Huang, Q Zhao, H Liu, Y Guo, H Xu
Journal of Molecular Neuroscience 2016
TGF-β regulates phosphorylation and stabilization of Sox9 protein in chondrocytes through p38 and Smad dependent mechanisms
G Coricor, R Serra
Scientific Reports 2016
A New Strategy to Deliver Synthetic Protein Drugs: Self-reproducible Biologics Using Minicircles
H Yi, Y Kim, J Kim, H Jung, YA Rim, SM Jung, SH Park, JH Ju
Scientific Reports 2014
A review of crosstalk between MAPK and Wnt signals and its impact on cartilage regeneration
Y Zhang, T Pizzute, M Pei
Cell and Tissue Research 2014
ECM stiffness primes the TGFβ pathway to promote chondrocyte differentiation
JL Allen, ME Cooke, T Alliston, K Luo
Molecular biology of the cell 2012
Deletion of Smad4 in fibroblasts leads to defective chondrocyte maturation and cartilage production in a TGFβ type II receptor independent manner
Y Teng, K Kanasaki, N Bardeesy, H Sugimoto, R Kalluri
Biochemical and Biophysical Research Communications 2011
GADD45beta enhances Col10a1 transcription via the MTK1/MKK3/6/p38 axis and activation of C/EBPbeta-TAD4 in terminally differentiating chondrocytes
K Tsuchimochi, M Otero, CL Dragomir, DA Plumb, LF Zerbini, TA Libermann, KB Marcu, S Komiya, K Ijiri, MB Goldring
The Journal of biological chemistry 2010
Reduced limb length and worsened osteoarthritis in adult mice after genetic inhibition of p38 MAP kinase activity in cartilage
S Namdari, L Wei, D Moore, Q Chen
Arthritis & Rheumatism 2008

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