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缺乏Dap12和αvβ3整合素会导致严重的骨硬化症。

Absence of Dap12 and the αvβ3 integrin causes severe osteopetrosis.

作者信息

Zou Wei, Teitelbaum Steven L

机构信息

Department of Pathology and Immunology, and Division of Bone and Mineral Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.

Department of Pathology and Immunology, and Division of Bone and Mineral Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110 Department of Pathology and Immunology, and Division of Bone and Mineral Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110

出版信息

J Cell Biol. 2015 Jan 5;208(1):125-36. doi: 10.1083/jcb.201410123. Epub 2014 Dec 29.

DOI:10.1083/jcb.201410123
PMID:25547154
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4284236/
Abstract

In vitro, ligand occupancy of αvβ3 integrin induces phosphorylation of Dap12, which is essential for osteoclast function. Like mice deleted of only αvβ3, Dap12(-/-) mice exhibited a slight increase in bone mass, but Dap12(-/-) mice, lacking another ITAM protein, FcRγ, were severely osteopetrotic. The mechanism by which FcRγ compensates for Dap12 deficiency is unknown. We find that co-deletion of FcRγ did not exacerbate the skeletal phenotype of β3(-/-) mice. In contrast, β3/Dap12 double-deficient (DAP/β3(-/-)) mice (but not β1/Dap12 double-deficient mice) were profoundly osteopetrotic, reflecting severe osteoclast dysfunction relative to those lacking αvβ3 or Dap12 alone. Activation of OSCAR, the FcRγ co-receptor, rescued Dap12(-/-) but not DAP/β3(-/-)osteoclasts. Thus, the absence of αvβ3 precluded compensation for Dap12 deficiency by FcRγ. In keeping with this, Syk phosphorylation did not occur in OSCAR-activated DAP/β3(-/-) osteoclasts. Thus, FcRγ requires the osteoclast αvβ3 integrin to normalize the Dap12-deficient skeleton.

摘要

在体外，αvβ3整合素的配体占据诱导Dap12磷酸化，这对破骨细胞功能至关重要。与仅缺失αvβ3的小鼠一样，Dap12基因敲除小鼠的骨量略有增加，但缺乏另一种免疫受体酪氨酸激活基序（ITAM）蛋白FcRγ的Dap12基因敲除小鼠出现严重的骨质石化。FcRγ补偿Dap12缺陷的机制尚不清楚。我们发现，共同缺失FcRγ并不会加重β3基因敲除小鼠的骨骼表型。相反，β3/Dap12双缺陷（DAP/β3-/-）小鼠（而非β1/Dap12双缺陷小鼠）出现严重的骨质石化，这反映出相对于仅缺乏αvβ3或Dap12的小鼠，其破骨细胞功能严重受损。FcRγ共受体OSCAR的激活挽救了Dap12基因敲除破骨细胞，但不能挽救DAP/β3-/-破骨细胞。因此，αvβ3的缺失排除了FcRγ对Dap12缺陷的补偿作用。与此一致的是，在OSCAR激活的DAP/β3-/-破骨细胞中未发生Syk磷酸化。因此，FcRγ需要破骨细胞αvβ3整合素来使Dap12缺陷的骨骼恢复正常。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c366/4284236/8e9215a4fdd7/JCB_201410123_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c366/4284236/a65afbed9cde/JCB_201410123_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c366/4284236/72e11ef69e5d/JCB_201410123_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c366/4284236/76f95a332f51/JCB_201410123_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c366/4284236/299c5a13b385/JCB_201410123_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c366/4284236/471481cb6ee7/JCB_201410123_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c366/4284236/f6325749004d/JCB_201410123_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c366/4284236/f1de711e3166/JCB_201410123_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c366/4284236/8e9215a4fdd7/JCB_201410123_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c366/4284236/a65afbed9cde/JCB_201410123_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c366/4284236/72e11ef69e5d/JCB_201410123_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c366/4284236/76f95a332f51/JCB_201410123_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c366/4284236/299c5a13b385/JCB_201410123_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c366/4284236/471481cb6ee7/JCB_201410123_Fig5.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c366/4284236/f1de711e3166/JCB_201410123_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c366/4284236/8e9215a4fdd7/JCB_201410123_Fig8.jpg

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