Nature Medcine：Atp6v0d2基因失活可减缓骨质疏松

生物谷

    生物谷报道：宾夕法尼亚州大学医学院的研究人员通过研究某个基因的功能，发现抑制骨衰老和刺激骨形成是可以同时发生的。这一观点可用于骨质疏松和其他骨疾病的治疗。该研究发表于Nature Medicine.杂志12月刊，由Yongwon Choi博士（宾夕法尼亚州大学病理和医学实验室教授）和他的同事共同完成。
   在美国，数以百万计的老年人患有骨质疏松，严重影响了他们的生活质量。随着人口的老龄化，骨质疏松将成为更大的问题。骨质疏松的治疗现在面临的主要挑战是，如何阻止骨衰老同时又促进骨生成。.目前，骨代谢的机制还不甚清楚，因此用于骨质疏松治疗的药物还不多。破骨细胞可引起骨衰老，大多数治疗骨质疏松的药物都是通过抑制破骨细胞而起作用的。但是，至少有一种药物是通过刺激成骨细胞而起作用，成骨细胞可促进骨形成。联合治疗不仅可以预防骨质疏松，而且可以改善骨质量。
    宾夕法尼亚州大学医学院的发现证明，抑制破骨细胞又同时促进新骨形成是可以实现的。骨骼健康是由破骨细胞和成骨细胞之间的动态平衡维系的。研究表明，小鼠Atp6v0d2基因的失活，导致骨量显著增加，其主要原因为破骨细胞功能缺失和骨形成增加。这些结果阐明了一些骨代谢的机制，并表明通过作用单个基因就可以既抑制骨衰老又同时促进骨形成。研究人员将对这个基因的上下游基因进行研究。如果能够找到作用于靶基因的药物，就可以帮助数百万的骨质疏松老年患者。

Figure 1. Deletion of Atp6v0d2 leads to defective osteoclasts and increased bone formation.

(a) Top, confirmation of Atp6v0d2 deletion by Southern blot. Genomic DNA from Atp6v0d2+/+(wild-type, WT), Atp6v0d2+/- and Atp6v0d2-/- mice was isolated, digested with SphI, and probed with "Probe 1" (see Supplementary Fig. 1). Wild-type and null alleles were 5 kb and 3.7 kb, respectively, in length. Middle, Atp6v0d2 RNA expression in osteoclasts. Bottom, Atp6v0d2 protein expression. Whole-cell extracts from wild-type osteoclast precursors (BMM) and from wild-type or Atp6v0d2-/- osteoclasts were examined with rabbit Atp6v0d2-specific polyclonal antibody by western blot analysis. (b) Tibias, femurs and vertebra from 8- to 10-week-old control, wild-type and Atp6v0d2-/- mice were examined by CT. Two-dimensional (left) and three-dimensional (right) reconstruction of femurs revealed increased bone mass in Atp6v0d2-/- mice compared with control littermates. Histograms represent three-dimensional trabecular structural parameters in the secondary spongiosa of the distal femur: bone volume fraction (BV/TV), trabecular number (Tb.N), trabecular spacing (Tb.Sp) and trabecular connectivity density (Conn-Dens). * P < 0.05. Data represent mean s.e.m. n = 6–8. (c) Static histomorphometry analysis of femurs from 6- to 7-week-old Atp6v0d2-/- mice and control littermates: bone volume (BV/TV), osteoclast surface per bone surface (OcS/BS), osteoblast surface per bone surface (ObS/BS) and osteoclast number per bone surface (NOc/BS). * P < 0.005, † P < 0.05. Data represent mean s.e.m. n = 4. (d) Serum TRACP5b levels were measured by ELISA. (e) Alcian blue staining on femurs from 6- to 7-week-old Atp6v0d2-/- mice and control littermates. (f) Serum type 1 collagen cross-linked telopeptide (CTX) measured by ELISA. * P < 0.05. (g) Dynamic histomorphometry analysis of femurs from 6- to 7-week-old Atp6v0d2-/- mice and control littermates: mineral apposition rate (MAR), bone formation rate (trabecular bone surface) (BFR/BS) and mineralizing surface (MS/BS). * P < 0.05, † P < 0.01. Data represent mean s.e.m. n = 4–5. Scale bar, 100 m. For values other than those presented here, see Supplementary Table 1. NS, not significant.

原文出处：

Nature Medcine December 2006, Volume 12 No 12

Published online: 26 November 2006; | doi:10.1038/nm1514

v-ATPase V0 subunit d2–deficient mice exhibit impaired osteoclast fusion and increased bone formation pp1403 - 1409
Seoung-Hoon Lee, Jaerang Rho, Daewon Jeong, Jai-Yoon Sul, Taesoo Kim, Nacksung Kim, Ju-Seob Kang, Takeshi Miyamoto, Toshio Suda, Sun-Kyeong Lee, Robert J Pignolo, Boguslawa Koczon-Jaremko, Joseph Lorenzo & Yongwon Choi
Published online: 26 November 2006 | doi:10.1038/nm1514
Abstract | Full text | PDF (641K) | Supplementary Information
See also: News and Views by Boyce & Xing

相关基因：

Atp6v0d2

Official Symbol: Atp6v0d2 and Name: ATPase, H+ transporting, lysosomal V0 subunit D2 [Mus musculus]

Other Aliases: 1620401A02Rik, AI324824, V-ATPase

Other Designations: ATPase, H+ transporting, V0 subunit D isoform 2; ATPase, H+ transporting, V0 subunit D, isoform 2; vacuolar proton-translocating ATPase d subunit d2

Chromosome: 4; Location: 4 A3

GeneID: 242341

ATP6V0D2

Official Symbol: ATP6V0D2 and Name: ATPase, H+ transporting, lysosomal 38kDa, V0 subunit d2 [Homo sapiens]

Other Aliases: ATP6D2, FLJ38708, VMA6

Other Designations: ATPase, H+ transporting, lysosomal 38kD, V0 subunit d isoform 2; ATPase, H+ transporting, lysosomal 38kDa, V0 subunit D2

Chromosome: 8

GeneID: 245972

作者简介：

Dr. Yongwon Choi, Ph.D.
Professor, Department of Pathology and Laboratory Medicine
Investigator, Abramson Family Cancer Research Institute
University of Pennsylvania School of Medicine
Room 308, BRB II/III
421 Curie Blvd.
Philadelphia, PA 19104

Research interests: http://www.uphs.upenn.edu/abramson/choi.html

最近， Choi博士，由于其在骨免疫学方面所做的贡献，获得了韩国著名的Ho-Am奖提名。Ho-Am奖授予那些做出杰出成就（促进学科长足发展并具有国际一流水准的成就）以及成为学术界楷模的学者和研究人员。Choi来自韩国汉城，2001年以来就职于宾夕法尼亚大学。

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