Hedgehog signaling orchestrates cartilage-to-bone transition independently of Smoothened
Hedgehog signaling orchestrates cartilage-to-bone transition independently of Smoothened
复制标题
Hedgehog 信号独立于 Smoothened 协调软骨到骨的转变
DOI：
10.1016/j.matbio.2022.04.006
复制
发表时间：
2022
期刊：
影响因子：
6.9
通讯作者：
Liu Yang
中科院分区：
文献类型：
--
作者：
Huanbo Wang;Chao Zheng;Weiguang Lu;Ting He;Jing Fan;Cheng Wang;Qiang Jie;Danny Chan;Kathryn Song Eng Cheah;Liu Yang
尽管最近的谱系研究强烈支持软骨细胞到成骨细胞的分化连续体，但其生物学意义和分子基础仍未确定。 单细胞水平的硅分析表明，在模拟软骨到骨的转变过程中，Hedgehog 相关转录组短暂关闭。受此启发，我们通过基因诱导功能的获得和丧失，以探究 Hedgehog 信号在软骨到骨转变中的作用。消融 Smoin 肥大软骨细胞 (HC) 不会导致任何表型结果，而删除 HC 中的 Ptch1 会导致原代海绵体形成破坏，并导致 HC 衍生的成骨细胞活跃增殖，从而导致成年突变小鼠中出现骨隆起。在 HC 衍生的成骨细胞中，Hedgehog 信号的组成性激活阻止其进一步分化为骨细胞。此外，HCs 中 Smo 和 Ptch1 的消融既不能逆转持续的 Hedgehog 信号传导，也不能逆转骨过度生长。这些结果确立了扩展的软骨细胞谱系对骨稳态和疾病的功能贡献，其由独立于 Smo 的 Hedgehog 信号传导的意外调节模式控制。
Although recent lineage studies strongly support a chondrocyte-to-osteoblast differentiation continuum, the biological significance and molecular basis remain undetermined.In silicoanalysis at a single-cell level indicates a transient shutdown of Hedgehog-related transcriptome during simulated cartilage-to-bone transition. Prompted by this, we genetically induce gain- and loss-of function to probe the role of Hedgehog signaling in cartilage-to-bone transition. AblatingSmoin hypertrophic chondrocytes (HCs) does not result in any phenotypic outcome, whereas deletingPtch1in HCs leads to disrupted formation of primary spongiosa and actively proliferating HCs-derived osteogenic cells that contribute to bony bulges seen in adult mutant mice. In HCs-derived osteoblasts, constitutive activation of Hedgehog signaling blocks their further differentiation to osteocytes. Moreover, ablation of bothSmoandPtch1in HCs reverses neither persistent Hedgehog signaling nor bone overgrowths. These results establish a functional contribution of extended chondrocyte lineage to bone homeostasis and diseases, governed by an unanticipated mode of regulation for Hedgehog signaling independently of Smo.