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Analysis of p38 MAP kinase pathway in osteoclasts

破骨细胞中p38 MAP激酶通路分析

基本信息

批准号：
17591955
负责人：
YAMASHITA Teruhito
金额：
$ 2.24万
依托单位：
Matsumoto Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591955/
关键词：
osteoclasts MAP kinase bone resorption survival Yeast Two Hybrid Screening p38 MAPキナーゼ MKK6 アデノウイルスベクター

项目摘要

Osteoclasts are derived from the monocyte/macrophage lineage and are responsible for bone resorption. p38 MAPK was essential for osteoclast differentiation but the survival and activation of osteoclasts were not affected by SB203580, a specific inhibitor for p38MAPK. Bone resorption factors such as IL-1 and lipopolysaccharide (LPS) activate MAPK signaling. To clarify the role of p38MAPK in osteoclast function, we measured the phosphorylated status of MAPKs and examined whether force-phosphorylation of p38MAPK modulates osteoclast function. Although osteoclasts expressed p38 MAPK at the level equivalent to that of bone marrow macrophages, phosphorylation of p38 MAPK was not induced by LPS in osteoclasts. MKK3 and MKK6, upstream kinases for p38 MAPK, were expressed in osteoclasts. Phosphorylation of MKK3/6 was not increased by IL-1 or LPS, even JNK and ERK were activated. Adenoviral expression of a constitutively active form of MKK6 (MKK6CA) in osteoclasts resulted in phosphorylation of p38 MAPK. The survival activity of MKK6CA-expressing osteoclasts evaluated at 48h was as high as that of IL-1-treated cells. Moreover, the number of survived osteoclasts which expressed MKK6CA decreased to a one third by SB203580. Neither bone resorbing activity on dentin slices nor the expression levels of cathepsin K were different between MKK6CA-expressing osteoclasts and control. These findings suggest that osteoclasts keep own p38 MAPK signaling in an inactive state to abort their survival. In a pathological state, p38 MAPK is activated in osteoclasts and it might extend osteoclast lifespan.

破骨细胞来源于单核细胞/巨噬细胞谱系，并负责骨吸收。p38 MAPK对破骨细胞的分化是必需的，但p38 MAPK的特异性抑制剂SB 203580对破骨细胞的存活和活化没有影响。骨吸收因子如IL-1和脂多糖（LPS）激活MAPK信号传导。为了阐明p38 MAPK在破骨细胞功能中的作用，我们测量了MAPK的磷酸化状态，并研究了p38 MAPK的强制磷酸化是否调节破骨细胞功能。虽然破骨细胞表达p38 MAPK的水平相当于骨髓巨噬细胞，磷酸化的p38 MAPK的破骨细胞中不诱导LPS。MKK 3和MKK 6是p38 MAPK的上游激酶，在破骨细胞中表达。IL-1和LPS均不能增加MKK 3/6的磷酸化水平，甚至能激活JNK和ERK。腺病毒表达的组成型活性形式的MKK 6（MKK 6CA）在破骨细胞导致磷酸化的p38 MAPK。在48小时评估的表达MKK 6CA的破骨细胞的存活活性与IL-1处理的细胞的存活活性一样高。此外，通过SB 203580，表达MKK 6CA的存活破骨细胞的数量减少至三分之一。牙本质切片上的骨吸收活性和组织蛋白酶K的表达水平在表达MKK 6CA的破骨细胞和对照组之间均无差异。这些结果表明，破骨细胞保持自己的p38 MAPK信号处于失活状态，以中止其生存。在病理状态下，p38 MAPK在破骨细胞中被激活，并可能延长破骨细胞的寿命。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dolomite supplementation improves bone metabolism through modulation of calcium-regulating hormone secretion in ovariectomized rats.

白云石补充剂通过调节卵巢切除大鼠的钙调节激素分泌来改善骨代谢。

DOI：
发表时间：
2005
期刊：
J Bone Miner Metab (in press)
影响因子：
0
作者：
Mizoguchi T et al.
通讯作者：
Mizoguchi T et al.

The mechanism of coupling between bone resorption and bone formation.

骨吸收与骨形成的耦合机制。

DOI：
发表时间：
2006
期刊：
J Oral Biosciences 48・(3)
影响因子：
0
作者：
Nakamichi Y et al.;Tsukiyama K et al.;Itoh S et al.;Yamamoto Y et al.;Udagawa N et al.
通讯作者：
Udagawa N et al.

Muramyl dipeptide enhsnces osteoclast formation induced by lipopolysaccharide, IL-1α and TNF-1α through nucleotide-binding oligomerization domain 2-mediated signaling in osteoblasts.

胞壁酰二肽通过成骨细胞中核苷酸结合寡聚化结构域 2 介导的信号传导增强脂多糖、IL-1α 和 TNF-1α 诱导的破骨细胞形成。

DOI：
发表时间：
2005
期刊：
J Immunol 175・3
影响因子：
0
作者：
Tokita;K;Inoue T.;Nakamichi Y et al.;Nakamichi Y et al.;Tsukiyama K et al.;Itoh S et al.;Yamamoto Y et al.;Udagawa N et al.;Okumura S et al.;Tsukiyama K et al.;Itoh S et al.;Yamamoto Y et al.;Udagawa N et al.;Okumura S et al.;Takahashi N et al.;Okumura S et al.;Mizoguchi T;Kobayashi Y;Kobayashi Y;Yang S
通讯作者：
Yang S

Gastric inhibitory polypeptide as an endogenous factor promoting new bone formation after food ingestion

DOI：
10.1210/me.2005-0187
发表时间：
2006-07-01
期刊：
MOLECULAR ENDOCRINOLOGY
影响因子：
0
作者：
Tsukiyama, Katsushi;Yamada, Yuichiro;Seino, Yutaka
通讯作者：
Seino, Yutaka

Osteoblasts provide a suitable microenvironment for the action of receptor activator of NF-κB ligand

成骨细胞为 NF-κB 配体受体激活剂的作用提供合适的微环境

DOI：
发表时间：
2006
期刊：
Endocrinology (In Press)
影响因子：
0
作者：
Ohno-Matsui K;Ichinose S;Nakahama K;Yoshida T;Kojima A;Mochizuki M;Morita I;Yamamoto Y.
通讯作者：
Yamamoto Y.