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PLoS Med.:锂元素可以促进骨骼愈合

来源:生物谷 2007-08-02 09:14

    最近一组科学家发现了一种全新的分子路径,这种分子路径对于受伤骨骼的愈合过程非常关键。同时科学家还发现锂元素能影响这一分子路径,从而可能将促进骨折病人的愈合。

    这一研究的主要负责人是来自加拿大多伦多儿童医院的Benjamin  Alman,他的小组主要研究了beta-catenin信号路径的作用,这一分子信号主要负责激活和T细胞因子相关的基因转录,而科学家们已经知道以上这一激活过程对于胚胎期间的骨骼形成起着关键的调控作用。

    通过研究发生了骨折的老鼠样本,小组的科研人员发现在骨折后的修复过程中,在骨骼和软骨的形成中这一信号基因转录的激活同时发生。而在缺少了此种分子信号路径的老鼠中,骨折的愈合过程则停止了,相反的,在此基因表达活跃的老鼠体内,骨骼生长的过程则大大加速。同时,科学家发现,对于骨折老鼠用锂进行治疗能激活此种信号,但是只有在骨折发生之后进行锂治疗才能有助于康复过程,而在骨折前使用锂则没有效果。 
    以上的这些研究结果显示beta-catenin功能在骨折修复的不同阶段并不一样。尽管研究的发现是否对于人类同样适用还需要进一步的确定,但是无疑用锂进行此种信号通路的激活确实有可能帮助促进骨折病人的愈合过程,并且仅限于在骨折愈合过程的较后期阶段。(教育部科技发展中心网)

英文原文:http://www.physorg.com/news104999444.html

原始出处:

PLoS Medicine

Received: February 1, 2007; Accepted: June 19, 2007; Published: July 31, 2007

Beta-Catenin Signaling Plays a Disparate Role in Different Phases of Fracture Repair: Implications for Therapy to Improve Bone Healing

Yan Chen1, Heather C. Whetstone1, Alvin C. Lin1, Puviindran Nadesan1, Qingxia Wei1, Raymond Poon1, Benjamin A. Alman1,2*

1 Program in Developmental and Stem Cell Biology, the Hospital for Sick Children, University of Toronto, Toronto, Canada, 2 Division of Orthopaedic Surgery, Department of Surgery, University of Toronto, Toronto, Canada

Background

Delayed fracture healing causes substantial disability and usually requires additional surgical treatments. Pharmacologic management to improve fracture repair would substantially improve patient outcome. The signaling pathways regulating bone healing are beginning to be unraveled, and they provide clues into pharmacologic management. The β-catenin signaling pathway, which activates T cell factor (TCF)-dependent transcription, has emerged as a key regulator in embryonic skeletogenesis, positively regulating osteoblasts. However, its role in bone repair is unknown. The goal of this study was to explore the role of β-catenin signaling in bone repair.

Methods and Findings

Western blot analysis showed significant up-regulation of β-catenin during the bone healing process. Using a β-Gal activity assay to observe activation during healing of tibia fractures in a transgenic mouse model expressing a TCF reporter, we found that β-catenin-mediated, TCF-dependent transcription was activated in both bone and cartilage formation during fracture repair. Using reverse transcription-PCR, we observed that several WNT ligands were expressed during fracture repair. Treatment with DKK1 (an antagonist of WNT/β-catenin pathway) inhibited β-catenin signaling and the healing process, suggesting that WNT ligands regulate β-catenin. Healing was significantly repressed in mice conditionally expressing either null or stabilized β-catenin alleles induced by an adenovirus expressing Cre recombinase. Fracture repair was also inhibited in mice expressing osteoblast-specific β-catenin null alleles. In stark contrast, there was dramatically enhanced bone healing in mice expressing an activated form of β-catenin, whose expression was restricted to osteoblasts. Treating mice with lithium activated β-catenin in the healing fracture, but healing was enhanced only when treatment was started subsequent to the fracture.

Conclusions

These results demonstrate that β-catenin functions differently at different stages of fracture repair. In early stages, precise regulation of β-catenin is required for pluripotent mesenchymal cells to differentiate to either osteoblasts or chondrocytes. Once these undifferentiated cells have become committed to the osteoblast lineage, β-catenin positively regulates osteoblasts. This is a different function for β-catenin than has previously been reported during development. Activation of β-catenin by lithium treatment has potential to improve fracture healing, but only when utilized in later phases of repair, after mesenchymal cells have become committed to the osteoblast lineage.

 Figure 1.β-Catenin-Mediated TCF-Dependent Transcription Is Activated during Fracture Healing

(A) Western blot analysis at different time points shows that β-catenin is elevated throughout healing in mice.

(B) β-catenin is also increased during human fracture healing.

(C–T) LacZ staining for TCF-dependent transcriptional activity in intact tibia (C–E); at 3 d following the tibia fracture (F–H); at 9 d following the fracture (I–K); at 2 wk following fracture (L–N); at 3 wk following fracture (O–Q); and at 5 wk following fracture (R–T). Images on the left (C, F, I, L, O, and R), at 25×, show the entire fracture callus (lines show the proximal and distal aspect of the fracture callus); in the center (D, G, J, M, P, and S) are 100× magnifications of areas shown in the boxes in the lower-magnification images; and on the right (E, H, K, N, Q, and T), the same images are magnified to 200×.

TCF-dependent transcriptional activity was maintained at a very low level in osteoblasts near the growth plate in normal intact tibia, and there was no positive staining in cells surrounding the mature bone tissue. Three days following fracture, very weak LacZ (barely detectable) staining was detected in mesenchymal tissues at the fracture site. Nine days following fracture, positive staining was evident mainly in cells surrounding cartilage matrix and osteoblasts along the trabeculae and periosteum. Chondrocytes and prehypertrophic chondrocytes also stained at 2 wk after the fracture. Osteoblasts consistently displayed strong staining signals at 2 and 3 wk following fracture. At the 5 wk time point, LacZ staining occurred mainly in osteoblasts in the periosteum either next to, or farther away from, the fracture site.

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