Docosahexaenoic acid signaling attenuates the proliferation and differentiation of bone marrow-derived osteoclast precursors and promotes apoptosis in mature osteoclasts.
Docosahexaenoic acid (DHA), a component of omega-3 fatty acids, has been reported to protect against inflammatory bone diseases such as osteoporosis and rheumatoid arthritis. However, its exact mechanism in bone resorbing cells has not been elucidated. In this study, we investigated the effects and the molecular mechanism of DHA on the proliferation, differentiation, and survival of osteoclast lineage cells using mouse bone marrow-derived macrophages (BMMs). DHA suppressed the macrophage colony-stimulating factor (M-CSF)-induced proliferation of osteoclast precursors, BMMs, in a dose-dependent manner. The attenuated proliferation of DHA-treated BMMs was related to M-CSF inhibition that selectively decreased Akt activation and downregulated cyclin D1 and cyclin D2 expression. DHA also blocked receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation from BMMs. At the molecular level, DHA inhibited JNK, ERK, and p38 MAPKs. In addition, it inhibited NF-κB signaling cascades, as demonstrated by the suppression of RANKL-mediated IκBα phosphorylation, NF-κB subunit p65 nuclear translocation, and NF-κB transcriptional activation. Accordingly, DHA attenuated the induction of c-Fos and nuclear factor of activated T cells c1 (NFATc1). Furthermore, DHA accelerated the apoptosis of mature osteoclasts by inducing Bim expression, a critical modulator of osteoclast apoptosis. Collectively, our data demonstrate that DHA exerts an anti-osteoclastogenic effect by suppressing the proliferation and differentiation of BMMs and enhancing the apoptosis of mature osteoclasts, thereby resulting in a diminished number of bone-resorptive cells.
Department of Biomedical Science, Cell and Matrix Research Institute, BK21 Plus KNU Biomedical Convergence Program, Clinical Trial Center, School of Medicine, Kyungpook National University and Hospital, Daegu 41944, Republic of Korea; Skeletal Diseases Genome Research Center, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea. Electronic address: biohjk@knu.ac.kr.
Hyun-Ju
HJ
Kim
Department of Biomedical Science, Cell and Matrix Research Institute, BK21 Plus KNU Biomedical Convergence Program, Clinical Trial Center, School of Medicine, Kyungpook National University and Hospital, Daegu 41944, Republic of Korea.
Boram
B
Ohk
Department of Biomedical Science, Cell and Matrix Research Institute, BK21 Plus KNU Biomedical Convergence Program, Clinical Trial Center, School of Medicine, Kyungpook National University and Hospital, Daegu 41944, Republic of Korea.
Hye Jin
HJ
Yoon
Department of Biomedical Science, Cell and Matrix Research Institute, BK21 Plus KNU Biomedical Convergence Program, Clinical Trial Center, School of Medicine, Kyungpook National University and Hospital, Daegu 41944, Republic of Korea.
Woo Youl
WY
Kang
Department of Biomedical Science, Cell and Matrix Research Institute, BK21 Plus KNU Biomedical Convergence Program, Clinical Trial Center, School of Medicine, Kyungpook National University and Hospital, Daegu 41944, Republic of Korea.
Sook Jin
SJ
Seong
Skeletal Diseases Genome Research Center, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea.
Shin-Yoon
SY
Kim
Department of Biomedical Science, Cell and Matrix Research Institute, BK21 Plus KNU Biomedical Convergence Program, Clinical Trial Center, School of Medicine, Kyungpook National University and Hospital, Daegu 41944, Republic of Korea. Electronic address: yry@knu.ac.kr.
Young-Ran
YR
Yoon
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000166:cytology*; D002454:Cell Differentiation / Q000187:drug effects*; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016213:Cyclins / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D053245:RANK Ligand / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism
D016213:Cyclins; D050778:NFATC Transcription Factors; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; D004281:Docosahexaenoic Acids; D016173:Macrophage Colony-Stimulating Factor; D051057:Proto-Oncogene Proteins c-akt
DHA; M-CSF; Osteoclast; RANKL