Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose:
Osteoblasts and osteoclasts play important roles in the bone remodeling. When the balance between these cells is disrupted, bone loss or aberrant bone formation occur. In rheumatoid arthritis (RA), pro-inflammatory cytokines such as TNF-α play a predominant role in joint destruction. We earlier reported that TNF-α inhibits bone morphogenetic protein (BMP)-induced osteoblast differentiation via activation of JNK and NF-κB pathways.
The fibroblast growth factor (FGF) family constitutes of at least 25 structurally related proteins and known to be involved in various biological processes including cell migration, differentiation, growth and survival. In particular, FGF-2, -8 and -18 have been implicated as key factors for the bone and cartilage homeostasis. It has also been reported that joint destruction of RA patients is involved in the increase of endogenous FGF-2 in synovial fluids.
Among the FGF family, FGF-8 is known to be a key regulator for limb development and cranial formation. However, functional relationship between FGF-8 and BMPs in the osteoblast differentiation and the signal interaction of FGF-8 and proinflammatory cytokines remain unclear. Here we studied the effects of FGF-8 in relation to TNF-α actions on BMP-2-induced osteoblast differentiation.
Methods:
Mouse myoblast cell line C2C12, osteoblast precursor cell line MC3T3-E1 and rat primary osteoblast were used to clarify the effects of FGF-8 and TNF-α on BMP-induced osteogenesis. Quantitative real-time PCR was performed to evaluate mRNA levels of osteoblast differentiation markers. Immunoblot analysis for the phosphorylation of Smads and MAPKs was performed to analyze the signal interaction induced by FGF-8, TNF-α and BMP-2.
Results:
We found that FGF-8 inhibited BMP-2-induced expression of osteoblast markers in a concentration-dependent manner. The efficacy of FGF-8 was smaller than that of TNF-α in the experiments using myoblast C2C12, MC3T3-E1 and rat osteoblasts. Of note, the inhibitory effects of FGF-8 on BMP-induced osteoblastic differentiation and Smad1/5/8 activation were enhanced under the co-treatment with TNF-α. FGF-8 also inhibited BMP-2-induced expression of Wnt5a, a non-canonical Wnt signaling, which is known to be involved in Smad-independent signaling induced by BMPs. FGF-8 had no influence on the expression levels of TNFRs, whereas FGF-8 increased the expression levels of ALK3 (BMPR1A) and reduced inhibitory Smads6/7, suggesting a possible feedback activity of FGF-8 to BMPR signaling. Moreover, a MEK inhibitor, but not JNK or NF-κB inhibitors, suppressed the FGF-8 actions on BMP-induced osteoblast differentiation.
Conclusion:
Collectively, it was uncovered that FGF-8 inhibits BMP-induced osteoblast differentiation via ERK pathway and the effects were amplified by TNF-α activity. This FGF-BMP interaction may be involved in the regulatory process of inflammatory bone damages as shown in RA.
Disclosure:
T. Katsuyama,
None;
F. Otsuka,
None;
M. Narazaki,
None;
K. E. Sada,
None;
K. Inagaki,
None;
J. Wada,
Astellas,
5,
Boehringer Ingelheim,
5,
Novartis Pharmaceutical Corporation,
8,
Novo Nordisk,
8,
Boehringer Ingelheim,
8;
H. Makino,
AbbVie,
5,
Astellas,
5,
Teijin,
5,
Boehringer Ingelheim,
8,
Chugai,
8,
Daiichi Sankyo,
8,
Dainippon Sumitomo,
8,
Kyowa Hakko Kirin,
8,
MSD,
8,
Novartis Pharmaceutical Corporation,
8,
Pfizer Inc,
8,
Takeda,
8,
Tanabe Mitsubish,
8,
Astellas,
2,
Boehringer Ingelheim,
2,
Daiichi Sankyo,
2,
Dainippon Sumitomo,
2,
Kyowa Hakko Kirin,
2,
Mochida,
2,
MSD,
2,
Novartis Pharmaceutical Corporation,
2,
Novo Nordisk,
2,
Pfizer Inc,
2,
Takeda,
2,
Tanabe Mitsubishi,
2,
Astellas,
8.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/interaction-of-fgf-8-and-tnf-a-in-the-regulation-of-bmp-induced-osteoblast-differentiation/