Schwartz Andrea G, Long Fanxin, Thomopoulos Stavros
Department of Orthopaedic Surgery, Washington University in St Louis, St Louis, MO 63110, USA.
Department of Orthopaedic Surgery, Washington University in St Louis, St Louis, MO 63110, USA Department of Medicine, Washington University in St Louis, St Louis, MO 63110, USA Department of Developmental Biology, Washington University in St Louis, St Louis, MO 63110, USA.
Development. 2015 Jan 1;142(1):196-206. doi: 10.1242/dev.112714.
Tendon attaches to bone across a specialized tissue called the enthesis. This tissue modulates the transfer of muscle forces between two materials, i.e. tendon and bone, with vastly different mechanical properties. The enthesis for many tendons consists of a mineralized graded fibrocartilage that develops postnatally, concurrent with epiphyseal mineralization. Although it is well described that the mineralization and development of functional maturity requires muscle loading, the biological factors that modulate enthesis development are poorly understood. By genetically demarcating cells expressing Gli1 in response to Hedgehog (Hh) signaling, we discovered a unique population of Hh-responsive cells in the developing murine enthesis that were distinct from tendon fibroblasts and epiphyseal chondrocytes. Lineage-tracing experiments revealed that the Gli1 lineage cells that originate in utero eventually populate the entire mature enthesis. Muscle paralysis increased the number of Hh-responsive cells in the enthesis, demonstrating that responsiveness to Hh is modulated in part by muscle loading. Ablation of the Hh-responsive cells during the first week of postnatal development resulted in a loss of mineralized fibrocartilage, with very little tissue remodeling 5 weeks after cell ablation. Conditional deletion of smoothened, a molecule necessary for responsiveness to Ihh, from the developing tendon and enthesis altered the differentiation of enthesis progenitor cells, resulting in significantly reduced fibrocartilage mineralization and decreased biomechanical function. Taken together, these results demonstrate that Hh signaling within developing enthesis fibrocartilage cells is required for enthesis formation.
肌腱通过一种称为附着点的特殊组织附着于骨骼。该组织调节两种具有截然不同力学特性的材料（即肌腱和骨骼）之间的肌肉力量传递。许多肌腱的附着点由出生后与骨骺矿化同时发育的矿化分级纤维软骨组成。尽管已有充分描述表明矿化和功能成熟的发育需要肌肉负荷，但调节附着点发育的生物学因素仍知之甚少。通过对响应刺猬信号通路（Hh）而表达Gli1的细胞进行基因标记，我们在发育中的小鼠附着点中发现了一群独特的Hh响应细胞，它们不同于肌腱成纤维细胞和骨骺软骨细胞。谱系追踪实验表明，子宫内起源的Gli1谱系细胞最终会占据整个成熟的附着点。肌肉麻痹增加了附着点中Hh响应细胞的数量，表明对Hh的反应性部分受肌肉负荷调节。在出生后第一周发育期间消融Hh响应细胞会导致矿化纤维软骨丧失，细胞消融5周后组织重塑极少。从发育中的肌腱和附着点中条件性删除对Ihh反应所必需的分子 smoothened，会改变附着点祖细胞的分化，导致纤维软骨矿化显著减少和生物力学功能下降。综上所述，这些结果表明发育中的附着点纤维软骨细胞内的Hh信号通路是附着点形成所必需的。
