title: Critical role of AKT protein in myeloma-induced osteoclast formation and osteolysis.
abstract: Abnormal osteoclast formation and osteolysis are the hallmarks of multiple myeloma (MM) bone disease, yet the underlying molecular mechanisms are incompletely understood. Here, we show that the AKT pathway was up-regulated in primary bone marrow monocytes (BMM) from patients with MM, which resulted in sustained high expression of the receptor activator of NF-κB (RANK) in osteoclast precursors. The up-regulation of RANK expression and osteoclast formation in the MM BMM cultures was blocked by AKT inhibition. Conditioned media from MM cell cultures activated AKT and increased RANK expression and osteoclast formation in BMM cultures. Inhibiting AKT in cultured MM cells decreased their growth and ability to promote osteoclast formation. Of clinical significance, systemic administration of the AKT inhibitor LY294002 blocked the formation of tumor tissues in the bone marrow cavity and essentially abolished the MM-induced osteoclast formation and osteolysis in SCID mice. The level of activating transcription factor 4 (ATF4) protein was up-regulated in the BMM cultures from multiple myeloma patients. Adenoviral overexpression of ATF4 activated RANK expression in osteoclast precursors. These results demonstrate a new role of AKT in the MM promotion of osteoclast formation and bone osteolysis through, at least in part, the ATF4-dependent up-regulation of RANK expression in osteoclast precursors.
authors.affiliation: From the College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Huiling
authors.initials: H
authors.lastname: Cao
authors.affiliation: From the College of Life Sciences, Nankai University, Tianjin 300071, China,; the Department of Biochemistry, Rush University, Chicago, Illinois 60612.
authors.forename: Ke
authors.initials: K
authors.lastname: Zhu
authors.affiliation: the State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases, Chinese Academy of Medical Sciences, Tianjin 300020, China.
authors.forename: Lugui
authors.initials: L
authors.lastname: Qiu
authors.affiliation: From the College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Li
authors.affiliation: From the College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Hanjie
authors.initials: H
authors.lastname: Niu
authors.affiliation: the State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases, Chinese Academy of Medical Sciences, Tianjin 300020, China.
authors.forename: Mu
authors.initials: M
authors.lastname: Hao
authors.affiliation: the Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15240, and.
authors.forename: Shengyong
authors.initials: S
authors.lastname: Yang
authors.affiliation: From the College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Zhongfang
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: the Department of Biochemistry, Rush University, Chicago, Illinois 60612.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Lai
authors.affiliation: Hematology/Oncology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Judith L
authors.initials: JL
authors.lastname: Anderson
authors.affiliation: the Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15240, and.
authors.forename: Jie
authors.initials: J
authors.lastname: Fan
authors.affiliation: the Department of Biochemistry, Rush University, Chicago, Illinois 60612.
authors.forename: Hee-Jeong
authors.initials: HJ
authors.lastname: Im
authors.affiliation: the Department of Biochemistry, Rush University, Chicago, Illinois 60612.
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.affiliation: Hematology/Oncology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: G David
authors.initials: GD
authors.lastname: Roodman
authors.affiliation: From the College of Life Sciences, Nankai University, Tianjin 300071, China,; the Department of Biochemistry, Rush University, Chicago, Illinois 60612,. Electronic address: Guozhi_Xiao@rush.edu.
authors.forename: Guozhi
authors.initials: G
authors.lastname: Xiao
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009025:Morpholines / Q000494:pharmacology; D009101:Multiple Myeloma / Q000201:enzymology* / Q000473:pathology; D009368:Neoplasm Transplantation; D010010:Osteoclasts / Q000201:enzymology* / Q000473:pathology; D010014:Osteolysis / Q000201:enzymology* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: C497109:ATF4 protein, human; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; D051701:Activating Transcription Factor 4; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; Bone; Metastasis; Osteoclast; Transcription Factors