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首页> 外文期刊>Molecular and Cellular Biology >A-Raf and B-Raf Are Dispensable for Normal Endochondral Bone Development, and Parathyroid Hormone-Related Peptide Suppresses Extracellular Signal-Regulated Kinase Activation in Hypertrophic Chondrocytes
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A-Raf and B-Raf Are Dispensable for Normal Endochondral Bone Development, and Parathyroid Hormone-Related Peptide Suppresses Extracellular Signal-Regulated Kinase Activation in Hypertrophic Chondrocytes

机译：A-Raf和B-Raf对于正常的内膜软骨发育是必不可少的，甲状旁腺激素相关肽抑制肥大软骨细胞中的细胞外信号调节的激酶活化。

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Parathyroid hormone-related peptide (PTHrP) and the parathyroid hormone-PTHrP receptor increase chondrocyte proliferation and delay chondrocyte maturation in endochondral bone development at least partly through cyclic AMP (cAMP)-dependent signaling pathways. Because data suggest that the ability of cAMP to stimulate cell proliferation involves the mitogen-activated protein kinase kinase kinase B-Raf, we hypothesized that B-Raf might mediate the proliferative action of PTHrP in chondrocytes. Though B-Raf is expressed in proliferative chondrocytes, its conditional removal from cartilage did not affect chondrocyte proliferation and maturation or PTHrP-induced chondrocyte proliferation and PTHrP-delayed maturation. Similar results were obtained by conditionally removing B-Raf from osteoblasts. Because A-raf and B-raf are expressed similarly in cartilage, we speculated that they may fulfill redundant functions in this tissue. Surprisingly, mice with chondrocytes deficient in both A-Raf and B-Raf exhibited normal endochondral bone development. Activated extracellular signal-regulated kinase (ERK) was detected primarily in hypertrophic chondrocytes, where C-raf is expressed, and the suppression of ERK activation in these cells by PTHrP or a MEK inhibitor coincided with a delay in chondrocyte maturation. Taken together, these results demonstrate that B-Raf and A-Raf are dispensable for endochondral bone development and they indicate that the main role of ERK in cartilage is to stimulate not cell proliferation, but rather chondrocyte maturation.
机译：甲状旁腺激素相关肽（PTHrP）和甲状旁腺激素-PTHrP受体至少部分通过循环AMP（cAMP）依赖性信号通路增加软骨内软骨发育中的软骨细胞增殖并延迟软骨细胞成熟。因为数据表明cAMP刺激细胞增殖的能力涉及丝裂原激活的蛋白激酶激酶激酶B-Raf，所以我们假设B-Raf可能介导了PTHrP在软骨细胞中的增殖作用。尽管B-Raf在增生的软骨细胞中表达，但有条件地将其从软骨中移除不会影响软骨细胞的增殖和成熟，也不会影响PTHrP诱导的软骨细胞增殖和PTHrP延迟的成熟。有条件地从成骨细胞中去除B-Raf可获得类似的结果。由于A- raf 和B- raf 在软骨中的表达相似，因此我们推测它们可能在此组织中发挥多余的功能。出人意料的是，软骨细胞缺乏A-Raf和B-Raf的小鼠表现出正常的软骨内骨发育。主要在肥大软骨细胞中检测到活化的细胞外信号调节激酶（ERK），表达C- raf ，并且通过PTHrP或MEK抑制剂抑制这些细胞中ERK的活化与延迟。软骨细胞成熟。综上，这些结果表明B-Raf和A-Raf对于软骨内骨骼发育是必不可少的，并且它们表明ERK在软骨中的主要作用不是刺激细胞增殖，而是刺激软骨细胞成熟。

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