C-type natriuretic peptide regulates endochondral bone growth through p38 MAP kinase-dependent and -independent pathways.
C-type natriuretic peptide regulates endochondral bone growth through p38 MAP kinase-dependent and -independent pathways.
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C型纳地尿肽通过p38 MAP激酶依赖性和非依赖性途径调节内软骨的骨生长。
DOI：
10.1186/1471-213x-7-18
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发表时间：
2007-03-20
影响因子：
--
通讯作者：
Beier, Frank
中科院分区：
文献类型：
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作者：
Agoston, Hanga;Khan, Sameena;James, Claudine G.;Gillespie, J. Ryan;Serra, Rosa;Stanton, Lee-Anne;Beier, Frank
C型利钠肽（CNP）是近年来发现的一种重要的软骨内骨生长的合成代谢调节剂，但其作用的分子机制尚不完全清楚。我们在胫骨器官培养系统中证明，p38的药理学抑制阻断CNP的合成代谢作用。我们进一步表明，CNP刺激软骨内骨生长主要是通过扩大肥大区的生长板，同时延迟矿化。这两种效应都被p38抑制逆转。我们还对显微切割的组织进行了Affyssin微阵列分析，以鉴定CNP靶基因。这些研究证实，肥大软骨细胞是生长板中CNP信号传导的主要靶标，因为在该区域中CNP调控的基因比其他区域多得多。虽然CNP受体在所有三个区域中以相似水平表达，但cGMP依赖性激酶I和II（CNP信号传导的重要转导物）在肥大细胞中的表达水平远高于胫骨其他区域，为CNP效应的空间分布提供了潜在解释。此外，我们的数据显示CNP诱导NPR3（一种利钠肽诱饵受体）的表达，表明存在限制CNP信号传导的反馈环。最后，我们的微阵列数据的详细分析表明，CNP调节BMP信号和细胞粘附中涉及的许多基因。我们的数据确定了CNP的新靶基因，并证明p38通路是CNP对软骨内骨生长影响的一种新的、必不可少的介质，对理解和治疗许多骨骼疾病具有潜在意义。
C-type natriuretic peptide (CNP) has recently been identified as an important anabolic regulator of endochondral bone growth, but the molecular mechanisms mediating its effects are not completely understood. We demonstrate in a tibia organ culture system that pharmacological inhibition of p38 blocks the anabolic effects of CNP. We further show that CNP stimulates endochondral bone growth largely through expansion of the hypertrophic zone of the growth plate, while delaying mineralization. Both effects are reversed by p38 inhibition. We also performed Affymetrix microarray analyses on micro-dissected tibiae to identify CNP target genes. These studies confirmed that hypertrophic chondrocytes are the main targets of CNP signaling in the growth plate, since many more genes were regulated by CNP in this zone than in the others. While CNP receptors are expressed at similar levels in all three zones, cGMP-dependent kinases I and II, important transducers of CNP signaling, are expressed at much higher levels in hypertrophic cells than in other areas of the tibia, providing a potential explanation for the spatial distribution of CNP effects. In addition, our data show that CNP induces the expression of NPR3, a decoy receptor for natriuretic peptides, suggesting the existence of a feedback loop to limit CNP signaling. Finally, detailed analyses of our microarray data showed that CNP regulates numerous genes involved in BMP signaling and cell adhesion. Our data identify novel target genes of CNP and demonstrate that the p38 pathway is a novel, essential mediator of CNP effects on endochondral bone growth, with potential implications for understanding and treatment of numerous skeletal diseases.