Mitogen-activated protein kinase phosphatase 1/dual specificity phosphatase 1 mediates glucocorticoid inhibition of osteoblast proliferation.
Mitogen-activated protein kinase phosphatase 1/dual specificity phosphatase 1 mediates glucocorticoid inhibition of osteoblast proliferation.
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DOI：
10.1210/me.2007-0153
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发表时间：
2007-12
期刊：
影响因子：
--
通讯作者：
Hulley PA
中科院分区：
文献类型：
--
作者：
Horsch K;de Wet H;Schuurmans MM;Allie-Reid F;Cato AC;Cunningham J;Burrin JM;Hough FS;Hulley PA
类固醇引起的骨质疏松症是糖皮质激素（GC）药物长期治疗的常见副作用。GC具有多种全身效应，可能影响骨代谢，但也通过减少增殖直接影响成骨细胞。这在低浓度下可能是有益的，增强了分化。然而，高剂量治疗在增生性成骨细胞室中产生严重缺陷。我们提供的因果关系的证据表明，这种影响GC介导的诱导的双特异性MAPK磷酸酶，MKP-1/DUSP 1。过量的MKP-1产生是必要的，也足以解释成骨细胞对有丝分裂原的反应受损。GC处理或转染后MKP-1的过表达消除了成骨细胞中的促有丝分裂反应。在体外去磷酸化试验前使用MKP-1的免疫耗竭或短干扰RNA转染敲低MKP-1可防止GC使ERK失活。c-jun N-末端激酶和p38 MAPK均未被20%胎牛血清中的促有丝分裂混合物激活，但它们被DNA损伤剂（UV照射）激活被GC处理或MKP-1过表达抑制，表明成骨细胞中MKP-1对所有三种MAPK的调节。然而，MAPK/ERK激酶-ERK通路的抑制剂抑制成骨细胞增殖，而c-jun N-末端激酶或p38 MAPK的抑制剂没有效果，这表明ERK是控制成骨细胞增殖的MAPK。MKP-1对ERK的调节为GC控制成骨细胞增殖提供了一种新的机制。
Steroid-induced osteoporosis is a common side effect of long-term treatment with glucocorticoid (GC) drugs. GCs have multiple systemic effects that may influence bone metabolism but also directly affect osteoblasts by decreasing proliferation. This may be beneficial at low concentrations, enhancing differentiation. However, high-dose treatment produces a severe deficit in the proliferative osteoblastic compartment. We provide causal evidence that this effect of GC is mediated by induction of the dual-specificity MAPK phosphatase, MKP-1/DUSP1. Excessive MKP-1 production is both necessary and sufficient to account for the impaired osteoblastic response to mitogens. Overexpression of MKP-1 after either GC treatment or transfection ablates the mitogenic response in osteoblasts. Knockdown of MKP-1 using either immunodepletion of MKP-1 before in vitro dephosphorylation assay or short interference RNA transfection prevents inactivation of ERK by GCs. Neither c-jun N-terminal kinase nor p38 MAPK is activated by the mitogenic cocktail in 20% fetal calf serum, but their activation by a DNA-damaging agent (UV irradiation) was inhibited by either GC treatment or overexpression of MKP-1, indicating regulation of all three MAPKs by MKP-1 in osteoblasts. However, an inhibitor of the MAPK/ERK kinase-ERK pathway inhibited osteoblast proliferation whereas inhibitors of c-jun N-terminal kinase or p38 MAPK had no effect, suggesting that ERK is the MAPK that controls osteoblast proliferation. Regulation of ERK by MKP-1 provides a novel mechanism for control of osteoblast proliferation by GCs.
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影响因子：
4.8
作者：
Divieti, P;Inomata, N;Bringhurst, FR
通讯作者：
Bringhurst, FR
DOI：
10.1084/jem.20051753
发表时间：
2006-01-23
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hammer M;Mages J;Dietrich H;Servatius A;Howells N;Cato AC;Lang R
通讯作者：
Lang R
影响因子：
4.8
作者：
Jaiswal, RK;Jaiswal, N;Pittenger, MF
通讯作者：
Pittenger, MF
DOI：
10.1089/oli.1.1996.6.169
发表时间：
1996-09-01
期刊：
ANTISENSE & NUCLEIC ACID DRUG DEVELOPMENT
影响因子：
--
作者：
Partridge, M;Vincent, A;Summerton, J
通讯作者：
Summerton, J
影响因子：
11.4
作者：
Kassel, O;Sancono, A;Cato, ACB
通讯作者：
Cato, ACB