title: Molecular mechanisms of the biphasic effects of interferon-γ on osteoclastogenesis.
abstract: Although interferon-γ (IFN-γ) potently inhibits osteoclastogenesis, the suppressive effect is significantly reduced when osteoclast precursors are pre-exposed to the receptor activator of NF-κB (RANK) ligand (RANKL). However, the molecular mechanism underlying the biphasic effects of IFN-γ on osteoclastogenesis remains elusive. Here, we recapitulate the biphasic functions of IFN-γ in osteoclastogenesis in both tissue culture dishes and on bone slices. We further demonstrate that IFN-γ markedly suppresses the RANKL-induced expression of nuclear factor of activated T-cells c1 (NFATc1) in normal, but not RANKL-pretreated bone marrow macrophages (BMMs). Similarly, IFN-γ impairs the activation of the nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) pathways in normal, but not RANKL-pretreated, BMMs. These findings indicate that IFN-γ inhibits osteoclastogenesis partially by suppressing the expression of NFATc1 and the activation of the NF-κB and JNK pathways. Moreover, IFN-γ inhibits the RANKL-induced expression of osteoclast genes, but RANKL pretreatment reprograms osteoclast genes into a state in which they can no longer be suppressed by IFN-γ, indicating that IFN-γ inhibits osteoclastogenesis by blocking the expression of osteoclast genes. Finally, the IVVY(535-538) motif in the cytoplasmic domain of RANK is responsible for rendering BMMs refractory to the inhibitory effect of IFN-γ. Taken together, these findings provide important mechanistic insights into the biphasic effects of IFN-γ on osteoclastogenesis.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Cheng
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Liu
authors.forename: Zhenqi
authors.initials: Z
authors.lastname: Shi
authors.forename: Joel
authors.initials: J
authors.lastname: Jules
authors.forename: Duorong
authors.initials: D
authors.lastname: Xu
authors.forename: Shaokai
authors.initials: S
authors.lastname: Luo
authors.forename: Shi
authors.initials: S
authors.lastname: Wei
authors.forename: Xu
authors.initials: X
authors.lastname: Feng
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism*; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D050778:NFATC Transcription Factors; D053245:RANK Ligand; D007371:Interferon-gamma