Li Na, Inoue Kazuki, Sun Jun, Niu Yingzhen, Lalani Sarfaraz, Yallowitz Alisha, Yang Xu, Zhang Chao, Shen Rong, Zhao Baohong, Xu Ren, Greenblatt Matthew B
1State Key Laboratory of Cellular Stress Biology, School of Medicine, Xiamen University, Xiamen, Fujian China.
2Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY USA.
Bone Res. 2020 Feb 19;8:11. doi: 10.1038/s41413-020-0086-3. eCollection 2020.
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 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，轴突导向因子SLIT3被确定为一种骨合成代谢因子。然而，这些报告在将成骨细胞与破骨细胞指定为骨骼SLIT3的关键产生者方面存在冲突，并且在SLIT3对破骨细胞生成的影响方面也提供了相互矛盾的数据。在此，为了解决这一差异，我们发现在人类或小鼠破骨细胞生成过程中没有可观察到的SLIT3表达，并且SLIT3对破骨细胞分化的影响仅为适度。在包括破骨细胞在内的组织蛋白酶K（CTSK）阳性细胞中条件性缺失SLIT3，对破骨细胞祖细胞数量、体外破骨细胞分化、总体骨量或骨吸收/形成参数没有影响。在包括破骨细胞谱系细胞在内的LysM阳性细胞中缺失SLIT3也观察到了类似结果。与此发现一致，由在破骨细胞发育的所有阶段都缺乏SLIT3表达的供体制备的骨髓嵌合体相对于对照显示出正常的骨量。综合来看，多条证据均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。
