Hedgehog signaling is essential for bone formation, including functioning as a means for the growth plate to drive skeletal mineralization. However, the mechanisms regulating hedgehog signaling specifically in bone-forming osteoblasts are largely unknown. Here, we identified SLIT and NTRK-like protein-5(Slitrk5), a transmembrane protein with few identified functions, as a negative regulator of hedgehog signaling in osteoblasts. Slitrk5 is selectively expressed in osteoblasts and loss of Slitrk5 enhanced osteoblast differentiation in vitro and in vivo. Loss of SLITRK5 in vitro leads to increased hedgehog signaling and overexpression of SLITRK5 in osteoblasts inhibits the induction of targets downstream of hedgehog signaling. Mechanistically, SLITRK5 binds to hedgehog ligands via its extracellular domain and interacts with PTCH1 via its intracellular domain. SLITRK5 is present in the primary cilium, and loss of SLITRK5 enhances SMO ciliary enrichment upon SHH stimulation. Thus, SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts that may be attractive as a therapeutic target to enhance bone formation.

Hedgehog 信号对于骨骼形成至关重要，包括作为生长板驱动骨骼矿化的一种手段。然而，专门在成骨成骨细胞中调节刺猬信号的机制在很大程度上是未知的。在这里，我们确定了 SLIT 和 NTRK 样蛋白-5（Slitrk5），一种功能很少的跨膜蛋白，作为成骨细胞中刺猬信号的负调节因子。Slitrk5 在成骨细胞中选择性表达，Slitrk5 缺失在体外和体内增强成骨细胞分化。体外 SLITRK5 的缺失导致刺猬信号增强，成骨细胞中 SLITRK5 的过表达抑制了刺猬信号下游靶标的诱导。从机制上讲，SLITRK5 通过其胞外域与刺猬配体结合，并通过其胞内域与 PTCH1 相互作用。SLITRK5 存在于初级纤毛中，SLITRK5 的缺失会在 SHH 刺激下增强 SMO 纤毛富集。因此，SLITRK5 是成骨细胞中刺猬信号的负调节因子，作为增强骨形成的治疗靶点可能很有吸引力。