Protein kinase C-delta deficiency perturbs bone homeostasis by selective uncoupling of cathepsin K secretion and ruffled border formation in osteoclasts.
Protein kinase C-delta deficiency perturbs bone homeostasis by selective uncoupling of cathepsin K secretion and ruffled border formation in osteoclasts.
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蛋白激酶C-delta缺乏通过在破骨细胞中的骨蛋白酶分泌和褶皱边界形成的选择性解偶联来使骨体内平衡。
DOI：
10.1002/jbmr.1701
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发表时间：
2012-12
影响因子：
6.2
通讯作者：
Faccio, Roberta
中科院分区：
文献类型：
--
作者：
Cremasco, Viviana;Decker, Corinne E.;Stumpo, Deborah;Blackshear, Perry J.;Nakayama, Keiichi I.;Nakayama, Keiko;Lupu, Traian S.;Graham, Daniel B.;Novack, Deborah V.;Faccio, Roberta
骨稳态需要破骨细胞的严格调节，破骨细胞分泌蛋白水解酶以降解骨基质。尽管最近在了解骨吸收如何发生方面取得了进展，但调节破骨细胞分泌的机制，特别是组织蛋白酶K囊泡的运输途径，仍然难以捉摸。利用遗传学方法，我们描述了PKCδ通过影响组织蛋白酶K胞吐作用调节骨吸收的需要。重要的是，PKCδ缺乏不会干扰皱褶边缘的形成或含有v-ATP酶的溶酶体囊泡的运输。从机制上讲，我们发现组织蛋白酶K的胞吐作用是由PKCδ通过调节肌动蛋白捆绑蛋白MARCKS来控制的。我们的发现的相关性在体内得到了强调，因为PKCδ−/−小鼠在实验性绝经后骨质疏松症模型中表现出骨量增加，并免受病理性骨丢失的影响。总的来说，我们的数据提供了新的机制见解的途径，选择性地促进分泌的组织蛋白酶K溶酶体独立的皱褶边界的形成，提供证据的存在多种机制，调节溶酶体胞吐破骨细胞。
Bone homeostasis requires stringent regulation of osteoclasts, which secrete proteolytic enzymes to degrade the bone matrix. Despite recent progress in understanding how bone resorption occurs, the mechanisms regulating osteoclast secretion, and in particular the trafficking route of cathepsin K vesicles, remain elusive. Using a genetic approach, we describe the requirement for PKCδ in regulating bone resorption by affecting cathepsin K exocytosis. Importantly, PKCδ deficiency does not perturb formation of the ruffled border or trafficking of lysosomal vesicles containing the v-ATPase. Mechanistically, we find that cathepsin K exocytosis is controlled by PKCδ through modulation of the actin bundling protein MARCKS. The relevance of our finding is emphasized in vivo as PKCδ−/− mice exhibit increased bone mass and are protected from pathological bone loss in a model of experimental post-menopausal osteoporosis. Collectively, our data provide novel mechanistic insights into the pathways that selectively promote secretion of cathepsin K lysosomes independently of ruffled border formation, providing evidence for the presence of multiple mechanisms that regulate lysosomal exocytosis in osteoclasts.
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影响因子：
3.7
作者：
Dumas F;Byrne RD;Vincent B;Hobday TM;Poccia DL;Larijani B
通讯作者：
Larijani B
影响因子：
5.3
作者：
Epple, Holly;Cremasco, Viviana;Faccio, Roberta
通讯作者：
Faccio, Roberta
影响因子：
6.2
作者：
Gowen, M;Lazner, F;Kola, I
通讯作者：
Kola, I
影响因子：
4
作者：
Collin, Olivier;Tracqui, Philippe;Planus, Emmanuelle
通讯作者：
Planus, Emmanuelle
影响因子：
7
作者：
Johnson, MR;Polymeropoulos, MH;Francomano, CA
通讯作者：
Francomano, CA