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Sphingosylphosphorylcholine blocks ovariectomy-induced bone loss by suppressing Ca2+/calmodulin-mediated osteoclast differentiation |
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| Authors: | Ha Young Lee Kwang Min Cho Min Kyung Kim Mingyu Lee Hun Kim Cheol Yong Choi Kyeong Kyu Kim Joon Seong Park Hong-Hee Kim Yoe-Sik Bae |
| Institution: | 1. Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea
Contribution: Conceptualization (equal), Data curation (equal), Formal analysis (equal), ?Investigation (equal), Writing - original draft (equal), Writing - review & editing (equal);2. Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea Contribution: Conceptualization (equal), Data curation (equal), Formal analysis (equal), ?Investigation (equal), Writing - original draft (equal);3. Department of Cell and Developmental Biology, BK21 Program and Dental Research Institute, Seoul National University, Seoul, Korea Contribution: Data curation (supporting), ?Investigation (supporting);4. Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea Contribution: Conceptualization (supporting), Data curation (supporting), ?Investigation (supporting);5. Department of Precision Medicine, Institute for Antimicrobial Resistance Research and Therapeutics, Sungkyunkwan University School of Medicine, Suwon, Korea Contribution: Data curation (supporting), Formal analysis (supporting), ?Investigation (supporting);6. Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea Contribution: Conceptualization (supporting), Writing - review & editing (supporting);7. Department of Precision Medicine, Institute for Antimicrobial Resistance Research and Therapeutics, Sungkyunkwan University School of Medicine, Suwon, Korea Contribution: Formal analysis (supporting), ?Investigation (supporting);8. Department of Hematology-Oncology, Ajou University School of Medicine, Suwon, Korea Contribution: Conceptualization (supporting), Resources (supporting);9. Department of Cell and Developmental Biology, BK21 Program and Dental Research Institute, Seoul National University, Seoul, Korea;10. Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea |
| Abstract: | Osteoporosis is a disease in which bone mineral density decreases due to abnormal activity of osteoclasts, and is commonly found in post-menopausal women who have decreased levels of female hormones. Sphingosylphosphorylcholine (SPC) is an important biological lipid that can be converted to sphingosine-1-phosphate (S1P) by autotaxin. S1P is known to be involved in osteoclast activation by stimulating osteoblasts, but bone regulation by SPC is not well understood. In this study, we found that SPC strongly inhibits RANKL-induced osteoclast differentiation. SPC-induced inhibitory effects on osteoclast differentiation were not affected by several antagonists of S1P receptors or pertussis toxin, suggesting cell surface receptor independency. However, SPC inhibited RANKL-induced calcineurin activation and subsequent NFATc1 activity, leading to decrease of the expression of Trap and Ctsk. Moreover, we found that bone loss in an experimental osteoporosis mouse model was recovered by SPC injection. SPC also blocked ovariectomy-induced body weight increase and Nfatc1 gene expression in mice. We also found that SPC inhibits RANKL-induced osteoclast differentiation in human macrophages. Since currently available treatments for osteoporosis, such as administration of female hormones or hormone receptor modulators, show serious side effects, SPC has potential as a new agent for osteoporosis treatment. |
| Keywords: | calcineurin osteoclast osteoporosis RANKL sphingosylphosphorylcholine |