最近一組科學(xué)家發(fā)現(xiàn)了一種全新的分子路徑,，這種分子路徑對于受傷骨骼的愈合過程非常關(guān)鍵,。同時科學(xué)家還發(fā)現(xiàn)鋰元素能影響這一分子路徑，從而可能將促進(jìn)骨折病人的愈合,。

    這一研究的主要負(fù)責(zé)人是來自加拿大多倫多兒童醫(yī)院的Benjamin  Alman,，他的小組主要研究了beta-catenin信號路徑的作用，這一分子信號主要負(fù)責(zé)激活和T細(xì)胞因子相關(guān)的基因轉(zhuǎn)錄,，而科學(xué)家們已經(jīng)知道以上這一激活過程對于胚胎期間的骨骼形成起著關(guān)鍵的調(diào)控作用,。

    通過研究發(fā)生了骨折的老鼠樣本，小組的科研人員發(fā)現(xiàn)在骨折后的修復(fù)過程中,，在骨骼和軟骨的形成中這一信號基因轉(zhuǎn)錄的激活同時發(fā)生,。而在缺少了此種分子信號路徑的老鼠中，骨折的愈合過程則停止了,，相反的,，在此基因表達(dá)活躍的老鼠體內(nèi)，骨骼生長的過程則大大加速,。同時,，科學(xué)家發(fā)現(xiàn)，對于骨折老鼠用鋰進(jìn)行治療能激活此種信號,，但是只有在骨折發(fā)生之后進(jìn)行鋰治療才能有助于康復(fù)過程,，而在骨折前使用鋰則沒有效果。
    以上的這些研究結(jié)果顯示beta-catenin功能在骨折修復(fù)的不同階段并不一樣,。盡管研究的發(fā)現(xiàn)是否對于人類同樣適用還需要進(jìn)一步的確定,，但是無疑用鋰進(jìn)行此種信號通路的激活確實(shí)有可能幫助促進(jìn)骨折病人的愈合過程,，并且僅限于在骨折愈合過程的較后期階段,。(教育部科技發(fā)展中心網(wǎng))

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

原始出處:

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.