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首页 » PLoS ONE报道 » Bone:耻骨松弛激素能加速由恶性肿瘤导致的骨骼损伤

Bone:耻骨松弛激素能加速由恶性肿瘤导致的骨骼损伤

来源:科学时报 2010-02-09 09:29

一个临床病理学家研究小组发现,一种类似于胰岛素的激素能够加速由恶性肿瘤导致的骨骼损伤。英国伦敦皇家学院的肿瘤学家Jonathan Waxman表示,“这项研究回答了一个基础问题。”一旦得到确认,这一研究成果最终将用于研制能够减缓或停止因癌症造成的骨损伤的药物。

作为一种激素,耻骨松弛激素已知与癌症有一定的关系。之前的研究将高水平的耻骨松弛激素与子宫癌和前列腺癌的扩散,以及那些能够蔓延到骨骼的癌症——例如乳腺癌、甲状腺癌和骨髓瘤——联系起来。然而由恶性肿瘤产生的耻骨松弛激素是否能够加速骨骼组织的破损却依然是个未解之谜。

意大利帕多瓦大学的临床病理学家Alberto Ferlin和Carlo Foresta与参与这项新研究的合作者表示,间接证据已证明了这种可能性。耻骨松弛激素属于一类由睾丸产生的名为INSL3的激素。在之前用人工培育的小鼠及人体细胞进行的研究工作中,Ferlin和同事已经发现,在某种情况下,INSL3能够与负责形成骨骼组织的造骨细胞相互作用。当睾丸无法生产足够的INSL3时,骨量便开始下降,骨质疏松症随即出现。Ferlin指出:“我们相信耻骨松弛激素也会引发一种类似的反应。最终,我们是对的。”

研究人员通过分析耻骨松弛激素对人工培育的人体骨细胞造成的影响从而证明了上述假设。他们发现,这种激素会刺激破骨细胞,而后者能够利用一种名为再吸收的机制来消除过多的骨骼组织,从而与造骨细胞的活动达成平衡。通过与破骨细胞表面的一种名为RXFP1的受体分子的结合,耻骨松弛激素会导致再吸收机制的完全失控,进而使破骨细胞消耗了太多的骨骼组织,并释放出了大量的钙。在人体中,这些钙进入血液会造成血钙过多,这是通常与骨转移一同出现的另一种严重损伤。研究人员还发现,耻骨松弛激素促进了不同肿瘤的生长、分化和扩散,对于那些能够引发骨转移的癌症尤为如此。

研究人员在细胞培养液中加入了一种耻骨松弛激素抗体,他们发现,后者能够防止该激素与受体的结合,以及由此造成的骨损伤。Foresta认为,这一发现表明,基于这种抗体的药物或是抑制耻骨松弛激素受体的药物能够在减缓骨损伤的同时防止血钙过多。研究人员在2月2日出版的《骨骼》杂志上报告了这一研究成果。

Waxman说:“这个发现太棒了,以至于让人怀疑它的真实性。”他认为,该成果是朝着有望停止骨癌扩散的治疗的“一个旅程的起点”,尽管找到这样一种药物的过程绝对不会是一次“短途旅行”。至于RXFP1的靶向治疗,Ferlin和Foresta表示,缩氨酸已经可以用于这一目的。但是他们也指出,一种以受体为设计目标的药物将是全新的,因此其副作用也是未知的。(生物谷Bioon.com)

生物谷推荐原始出处:

Bone Volume 46, Issue 2, February 2010, Pages 504-513

Relaxin stimulates osteoclast differentiation and activation

Alberto Ferlina, Anastasia Pepea, Arianna Facciollia, Lisa Gianeselloa and Carlo Foresta, a,

a Section of Clinical Pathology and Center for Male Gamete Cryopreservation, Department of Histology, Microbiology and Medical Biotechnologies, University of Padova, Via Gabelli 63, 35121 Padova, Italy

Relaxin is a pleiotropic hormone with actions in reproductive and non-reproductive tissues, and has a role in tumor biology. It can promote growth, differentiation and invasiveness of different tumors, especially those that give bone metastases, and relaxin serum concentrations are increased in patients with bone metastasis. In osteolytic metastasis the destruction of bone is mediated by osteoclasts that are multinucleated cells derived from hematopoietic progenitors. We found that human hematopoietic precursors and mature osteoclasts express the relaxin receptor RXFP1. Then, we investigated the effects of relaxin on the differentiation, activation and gene expression of osteoclasts during in vitro osteoclastogenesis from human hematopoietic progenitor cells. Relaxin alone was able to induce the multistep differentiation process of human osteoclastogenesis with timing similar to that obtained with the classical stimulators of osteoclastogenesis RANKL, M-CSF and PTH. The expression profile of several osteoclast genes was studied with quantitative RT-PCR during the entire process of osteoclastogenesis. This analysis showed that relaxin induced genes that are implicated in the differentiation, survival and activation of osteoclasts. Relaxin-induced osteoclasts were fully differentiated, positive for tartrate resistant acid phosphatase and vitronectin receptor, expressing a typical F-actin ring and able to resorb the bone. Furthermore, relaxin induced the expression of its specific receptor RXFP1 in osteoclasts. This study demonstrates for the first time that relaxin is a potent stimulator of osteoclastogenesis from hematopoietic precursors and regulates the activity of mature osteoclasts, opening new perspectives on the role of this hormone in bone physiology, diseases and metastasis.

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