Tendon-derived cathepsin K-expressing progenitor cells activate Hedgehog signaling to drive heterotopic ossification
Tendon-derived cathepsin K-expressing progenitor cells activate Hedgehog signaling to drive heterotopic ossification
复制标题
表达肌腱组织蛋白酶 K 的祖细胞激活 Hedgehog 信号传导以驱动异位骨化
DOI：
10.1172/jci132518
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发表时间：
2020-12-01
影响因子：
15.9
通讯作者：
Zou, Weiguo
中科院分区：
文献类型：
--
作者：
Feng, Heng;Xing, Wenhui;Zou, Weiguo
异位骨化（HO）是一种病理性骨形成，其特征是肌肉、肌腱或其他软组织内的骨化。然而，HO发病机制中涉及的细胞起源和机制仍然难以捉摸。在这里，我们表明，在组织蛋白酶K-Cre表达（Ctsk-Cre表达）细胞中的融合抑制基因（Sufu）的缺失导致自发和进行性韧带，肌腱和关节周围骨化。谱系追踪研究和细胞功能分析表明，Ctsk-Cre可以标记由肌腱标记物Scleraxis（Scx）标记的肌腱衍生祖细胞（TDPCs）亚群。Ctsk（+）Scx（+）TDPC富含肌腱干细胞标记物，并显示出最高的自我更新能力和分化潜力。腐乳缺乏通过上调Hedgehog（Hh）信号传导引起表达Ctsk-Cre的腱源性细胞的成软骨和成骨分化增强。此外，使用JQ 1对Hh信号传导进行药物干预抑制了HO的发展。因此，我们的研究结果表明，Ctsk-Cre标记的TDPC亚群有助于HO和他们的细胞命运的变化是由激活Hh信号。
Heterotopic ossification (HO) is pathological bone formation characterized by ossification within muscle, tendons, or other soft tissues. However, the cells of origin and mechanisms involved in the pathogenesis of HO remain elusive. Here we show that deletion of suppressor of fused (Sufu) in cathepsin K-Cre-expressing (Ctsk-Cre-expressing) cells resulted in spontaneous and progressive ligament, tendon, and periarticular ossification. Lineage tracing studies and cell functional analysis demonstrated that Ctsk-Cre could label a subpopulation of tendon-derived progenitor cells (TDPCs) marked by the tendon marker Scleraxis (Scx). Ctsk(+)Scx(+) TDPCs are enriched for tendon stem cell markers and show the highest self-renewal capacity and differentiation potential. Sufu deficiency caused enhanced chondrogenic and osteogenic differentiation of Ctsk-Cre-expressing tendon-derived cells via upregulation of Hedgehog (Hh) signaling. Furthermore, pharmacological intervention in Hh signaling using JQ1 suppressed the development of HO. Thus, our results show that Ctsk-Cre labels a subpopulation of TDPCs contributing to HO and that their cell-fate changes are driven by activation of Hh signaling.