The axon guidance cue SLIT3 was identified as an osteoanabolic agent in two recent reports. However, these reports conflict in their nomination of osteoblasts versus osteoclasts as the key producers of skeletal SLIT3 and additionally offer conflicting data on the effects of SLIT3 on osteoclastogenesis. Here, aiming to address this discrepancy, we found no observable SLIT3 expression during human or mouse osteoclastogenesis and the only modest SLIT3-mediated effects on osteoclast differentiation. Conditional deletion of SLIT3 in cathepsin K (CTSK)-positive cells, including osteoclasts, had no effect on the number of osteoclast progenitors, in vitro osteoclast differentiation, overall bone mass, or bone resorption/formation parameters. Similar results were observed with the deletion of SLIT3 in LysM-positive cells, including osteoclast lineage cells. Consistent with this finding, bone marrow chimeras made from Slit3^−/− donors that lacked SLIT3 expression at all stages of osteoclast development displayed normal bone mass relative to controls. Taken in context, multiple lines of evidence were unable to identify the physiologic function of osteoclast-derived SLIT3, indicating that osteoblasts are the major source of skeletal SLIT3.

在最近的两份报告中，轴突引导线索 SLIT3 被确定为骨合成代谢剂。然而，这些报告在提名成骨细胞与破骨细胞作为骨骼 SLIT3 的主要生产者方面存在冲突，另外还提供了关于 SLIT3 对破骨细胞生成影响的相互矛盾的数据。在这里，为了解决这种差异，我们发现在人或小鼠破骨细胞生成过程中没有可观察到的 SLIT3 表达，并且只有 SLIT3 介导的对破骨细胞分化的适度影响。在组织蛋白酶 K (CTSK) 阳性细胞（包括破骨细胞）中条件性删除 SLIT3 对破骨细胞祖细胞的数量、体外破骨细胞分化、总骨量或骨吸收/形成参数没有影响。在 LysM 阳性细胞（包括破骨细胞谱系细胞）中删除 SLIT3 也观察到类似的结果。在破骨细胞发育的所有阶段都缺乏 SLIT3 表达的Slit3 ^-/-供体相对于对照显示出正常的骨量。在上下文中，多条证据无法确定破骨细胞衍生的 SLIT3 的生理功能，表明成骨细胞是骨骼 SLIT3 的主要来源。