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Sphingosine-1-phosphate (S1P) is an anabolic clastokine. Sphingosine kinase (SPHK) is the rate-limiting enzyme in S1P production and has 2 isoforms. To evaluate the roles of SPHK1 and SPHK2 in bone, we examined the skeletal phenotype of mice with selective deletion of SPHK1 in osteoclasts (SPHK1-Oc−/−) and mice in which the SPHK2 gene was deleted in all tissues (SPHK2−/−). SPHK1-Oc−/− had normal bone mass. By contrast, SPHK2−/− female mice had a 14% lower spinal bone mineral density (BMD; P &amp;lt; 0.01) and males a 22% lower BMD at the same site (P &amp;lt; 0.001). SPHK2−/− and control mice were subsequently treated either with daily parathyroid hormone [PTH](1-34) or vehicle for 29 days. The response to PTH was significantly attenuated in the SPHK2−/−mice. The mean femoral bone volume to total volume fraction (BV/TV) increased by 24.8% in the PTH-treated female control animals vs 10.6% in the vehicle-treated female controls (P &amp;lt; 0.01). In contrast, in the SPHK2−/− female mice the difference in femoral trabecular BV/TV at the end of treatment was not significant (20.5 vs13.3%, PTH vs vehicle, P = NS). The anabolic response to PTH was significantly attenuated in the spine of male SPHK2−/− mice (29.7% vs 23.1%, PTH vs vehicle, in controls, P &amp;lt; 0.05; 26.9% vs 19.5% PTH vs vehicle in SPHK2−/− mice, P = NS). The spine responded normally in the SPHK2−/− female mice. Interestingly, suppression of sclerostin was blunted in the SPHK2−/− mice when those animals were treated with an anabolic PTH regimen. We conclude that SPHK2 has an important role in mediating both normal bone remodeling and the anabolic response to PTH.

An Unanticipated Role for Sphingosine Kinase-2 in Bone and in the Anabolic Effect of Parathyroid Hormone