Abstract
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.
Highlights
Drugs for the treatment of skeletal disorders, such as osteoporosis, typically fall into one of two categories
Axon guidance cues have emerged as agents of great interest in this regard, as they control bone formation by a variety of mechanisms, including shaping the skeletal microenvironment to support osteogenesis.[3,4,5,6,7]
The expression of SLIT3 in osteoclastogenesis To clarify the cellular sources of SLIT3, we first examined Slit[3] expression in parallel with other osteoclast makers using real-time PCR during in vitro osteoclastogenesis
Summary
Drugs for the treatment of skeletal disorders, such as osteoporosis, typically fall into one of two categories. The effect of recombinant SLIT3 on osteoclastogenesis in vitro To assess the effects of exogenous SLIT3 on osteoclastogenesis, deleter strain LysM-cre in which osteoclasts were targeted in addition to macrophages and neutrophils (Slit3lysM).[21] Similar to observations in Slit3ctsk mice, female Slit3lysM mice at 8 weeks of we treated wild-type BMMs undergoing osteoclast differentiation age did not show a discernible change in bone mass accrual with recombinant SLIT3 at a level that showed bioactivity in multiple other cellular assays (1 μg·mL−1), including tube formation assays in endothelial cells.[8,11,15] SLIT3 treatment (Fig. 5a, b).
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