title: Cobalt protoporphyrin represses osteoclastogenesis through blocking multiple signaling pathways.
abstract: Cobalt protoporphyrin (CoPP) is a metallo-protoporphyrin that works as a powerful inducer of heme oxigenase-1 (HO-1) in various tissues and cells. Our recent studies have demonstrated that induction of HO-1 by several reagents inhibited differentiation and activation of osteoclasts (OCLs), which are multinucleated bone resorbing cells. However, the effects of CoPP on osteoclastogenesis remain to be elucidated. In this study, we report that CoPP inhibits receptor activator of nuclear factor κB ligand (RANKL)-induced OCL formation in a dose dependent manner. Importantly, CoPP had little cytotoxicity, but rather enhanced cell proliferation of OCLs. CoPP suppressed the protein levels of nuclear factor of activated T cells cytoplasmic-1 (NFATc1) as well as those of OCLs markers such as Src and cathepsin K, which are transcriptionally regulated by NFATc1 in mature OCLs. Western blot analyses also showed that CoPP abolished RANKL-stimulated phosphorylation of several major signaling pathways such as IκB, Akt, ERK, JNK and p38 MAPKs in OCL precursor cells. Thus, our results show that CoPP represses osteoclastogenesis through blocking multiple signaling pathways.
authors.affiliation: Division of Dental Pharmacology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1, Sakamoto, Nagasaki, 852-8588, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Yashima
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Okamoto
authors.forename: Eiko
authors.initials: E
authors.lastname: Sakai
authors.forename: Mayumi
authors.initials: M
authors.lastname: Iwatake
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Fukuma
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Nishishita
authors.forename: Takayuki
authors.initials: T
authors.lastname: Tsukuba
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011524:Protoporphyrins / Q000737:chemistry / Q000494:pharmacology*; D053245:RANK Ligand / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D011524:Protoporphyrins; D053245:RANK Ligand; C007095:cobaltiprotoporphyrin