Kuwahara Stephanie T, Liu Shuwan, Chareunsouk Andrew, Serowoky Maxwell, Mariani Francesca V
University of Southern California, Keck School of Medicine, Department of Stem Cell Biology and Regenerative Medicine, Los Angeles, CA, 90033, USA.
Bone Res. 2022 Feb 15;10(1):13. doi: 10.1038/s41413-021-00184-8.
Uncovering the molecular pathways that drive skeletal repair has been an ongoing challenge. Initial efforts have relied on in vitro assays to identify the key signaling pathways that drive cartilage and bone differentiation. While these assays can provide some clues, assessing specific pathways in animal models is critical. Furthermore, definitive proof that a pathway is required for skeletal repair is best provided using genetic tests. Stimulating the Hh (Hedgehog) pathway can promote cartilage and bone differentiation in cell culture assays. In addition, the application of HH protein or various pathway agonists in vivo has a positive influence on bone healing. Until recently, however, genetic proof that the Hh pathway is involved in bone repair has been lacking. Here, we consider both in vitro and in vivo studies that examine the role of Hh in repair and discuss some of the challenges inherent in their interpretation. We also identify needed areas of study considering a new appreciation for the role of cartilage during repair, the variety of cell types that may have differing roles in repair, and the recent availability of powerful lineage tracing techniques. We are optimistic that emerging genetic tools will make it possible to precisely define when and in which cells promoting Hh signaling can best promote skeletal repair, and thus, the clinical potential for targeting the Hh pathway can be realized.
揭示驱动骨骼修复的分子途径一直是一项持续存在的挑战。最初的努力依赖于体外试验来确定驱动软骨和骨分化的关键信号通路。虽然这些试验能提供一些线索，但在动物模型中评估特定通路至关重要。此外，使用基因测试能最好地提供某一通路对骨骼修复必不可少的确切证据。在细胞培养试验中，刺激Hh（刺猬索尼克）通路可促进软骨和骨分化。此外，在体内应用HH蛋白或各种通路激动剂对骨愈合有积极影响。然而，直到最近，仍缺乏Hh通路参与骨修复的基因证据。在此，我们考虑了体外和体内研究，这些研究探讨了Hh在修复中的作用，并讨论了其解读中固有的一些挑战。我们还根据对修复过程中软骨作用的新认识、可能在修复中发挥不同作用的多种细胞类型以及强大的谱系追踪技术的最新可用性，确定了需要研究的领域。我们乐观地认为，新兴的基因工具将使精确界定何时以及在哪些细胞中促进Hh信号传导能最佳地促进骨骼修复成为可能，因此，靶向Hh通路的临床潜力能够得以实现。
