Institute of Medicine, Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
JCI Insight. 2024 Feb 13;9(6):e165226. doi: 10.1172/jci.insight.165226.
Recently, skeletal stem cells were shown to be present in the epiphyseal growth plate (epiphyseal skeletal stem cells, epSSCs), but their function in connection with linear bone growth remains unknown. Here, we explore the possibility that modulating the number of epSSCs can correct differences in leg length. First, we examined regulation of the number and activity of epSSCs by Hedgehog (Hh) signaling. Both systemic activation of Hh pathway with Smoothened agonist (SAG) and genetic activation of Hh pathway by Patched1 (Ptch1) ablation in Pthrp-creER Ptch1fl/fl tdTomato mice promoted proliferation of epSSCs and clonal enlargement. Transient intra-articular administration of SAG also elevated the number of epSSCs. When SAG-containing beads were implanted into the femoral secondary ossification center of 1 leg of rats, this leg was significantly longer 1 month later than the contralateral leg implanted with vehicle-containing beads, an effect that was even more pronounced 2 and 6 months after implantation. We conclude that Hh signaling activates growth plate epSSCs, which effectively leads to increased longitudinal growth of bones. This opens therapeutic possibilities for the treatment of differences in leg length.
最近，骺板（骺板骨骼干细胞，epSSCs）中存在成骨干细胞已被证实，但它们在与线性骨生长相关的功能仍不清楚。在这里，我们探讨了调节 epSSCs 数量是否可以纠正腿长差异的可能性。首先，我们研究了 Hedgehog (Hh) 信号通路对 epSSCs 的数量和活性的调节作用。全身性激活 Hh 通路（用 Smoothened 激动剂 SAG）和在 Pthrp-creER Ptch1fl/fl tdTomato 小鼠中遗传激活 Hh 通路（通过敲除 Patched1，Ptch1）均可促进 epSSCs 的增殖和克隆扩增。短暂的关节内给予 SAG 也增加了 epSSCs 的数量。当 SAG 包含的珠子被植入大鼠 1 条腿的股骨次级骨化中心时，1 个月后这条腿明显比植入含有载体珠子的对侧腿长，植入后 2 个月和 6 个月时效果更加明显。我们的结论是，Hh 信号激活生长板中的 epSSCs，这有效地导致骨骼的纵向生长增加。这为治疗腿长差异提供了治疗可能性。
