Gregory Carl A, Gunn William G, Reyes Emigdio, Smolarz Angela J, Munoz James, Spees Jeffrey L, Prockop Darwin J
Center for Gene Therapy, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
Ann N Y Acad Sci. 2005 May;1049:97-106. doi: 10.1196/annals.1334.010.
Human mesenchymal stem cells (hMSCs) from bone marrow are a source of osteoblast progenitors in vivo, and under appropriate conditions they differentiate into osteoblasts ex vivo. The cells provide a convenient cell culture model for the study of osteogenic tissue repair in an experimentally accessible system. Recent advances in the field of skeletal development and osteogenesis have demonstrated that signaling through the canonical wingless (Wnt) pathway is critical for the differentiation of progenitor cell lines into osteoblasts. Inhibition of such signals can predispose hMSCs to cell cycle entry and prevent osteogenesis. Our investigation of the role of Wnt signaling in osteogenesis by hMSCs ex vivo has demonstrated that osteogenesis proceeds in response to bone morphogenic protein 2 stimulation and is sustained by Wnt signaling. In the presence of Dkk-1, an inhibitor of Wnt signaling, the cascade is disrupted, resulting in inhibition of osteogenesis. Peptide mapping studies have provided peptide Dkk-1 agonists and the opportunity for the production of blocking antibodies. Anti-Dkk-1 strategies are clinically relevant since high serum levels of Dkk-1 are thought to contribute to osteolytic lesion formation in multiple myeloma and possibly some forms of osteosarcoma. Specific inhibitors of glycogen synthetase kinase 3beta (GSK3beta), which mimic Wnt signaling, may also have a therapeutic benefit by enhancing in vitro osteogenesis despite the presence of Dkk-1. Antibodies that block Dkk-1 and GSK3beta inhibitors may provide novel opportunities for the enhancement of bone repair in a variety of human diseases such as multiple myeloma and osteosarcoma.
来自骨髓的人间充质干细胞（hMSCs）是体内成骨细胞祖细胞的来源，在适当条件下它们可在体外分化为成骨细胞。这些细胞为在实验可及系统中研究成骨组织修复提供了便捷的细胞培养模型。骨骼发育和成骨领域的最新进展表明，通过经典无翅型（Wnt）信号通路的信号传导对于祖细胞系分化为成骨细胞至关重要。抑制此类信号会使hMSCs易于进入细胞周期并阻止成骨。我们对hMSCs体外成骨过程中Wnt信号作用的研究表明，成骨过程在骨形态发生蛋白2刺激下进行，并由Wnt信号维持。在存在Wnt信号抑制剂Dickkopf-1（Dkk-1）的情况下，该级联反应被破坏，导致成骨受到抑制。肽图谱研究提供了Dkk-1肽激动剂，并为生产阻断抗体提供了机会。抗Dkk-1策略具有临床相关性，因为高血清水平的Dkk-1被认为与多发性骨髓瘤以及可能某些形式的骨肉瘤中的溶骨性病变形成有关。模仿Wnt信号的糖原合酶激酶3β（GSK3β）特异性抑制剂，尽管存在Dkk-1，但通过增强体外成骨作用也可能具有治疗益处。阻断Dkk-1的抗体和GSK3β抑制剂可能为增强多种人类疾病（如多发性骨髓瘤和骨肉瘤）中的骨修复提供新的机会。
