title: FGF23 is elevated in multiple myeloma and increases heparanase expression by tumor cells.
abstract: Multiply myeloma (MM) grows in and destroys bone, where osteocytes secrete FGF23, a hormone which affects phosphate homeostasis and aging. We report that multiple myeloma (MM) cells express receptors for and respond to FGF23. FGF23 increased mRNA for EGR1 and its target heparanase, a pro-osteolytic factor in MM. FGF23 signals through a complex of klotho and a classical FGF receptor (FGFR); both were expressed by MM cell lines and patient samples. Bone marrow plasma cells from 42 MM patients stained positively for klotho, while plasma cells from 8 patients with monoclonal gammopathy of undetermined significance (MGUS) and 6 controls were negative. Intact, active FGF23 was increased 2.9X in sera of MM patients compared to controls. FGF23 was not expressed by human MM cells, but co-culture with mouse bone increased its mRNA. The FGFR inhibitor NVP-BGJ398 blocked the heparanase response to FGF23. NVP-BGJ398 did not inhibit 8226 growth in vitro but significantly suppressed growth in bone and induction of the osteoclast regulator RANK ligand, while decreasing heparanase mRNA. The bone microenvironment provides resistance to some anti-tumor drugs but increased the activity of NVP-BGJ398 against 8226 cells. The FGF23/klotho/heparanase signaling axis may offer targets for treatment of MM in bone.
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.|Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA.
authors.forename: Attaya
authors.initials: A
authors.lastname: Suvannasankha
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Tompkins
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Edwards
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Katarina V
authors.initials: KV
authors.lastname: Petyaykina
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Colin D
authors.initials: CD
authors.lastname: Crean
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Pierrick G
authors.initials: PG
authors.lastname: Fournier
authors.affiliation: Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Jamie M
authors.initials: JM
authors.lastname: Parker
authors.affiliation: Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: George E
authors.initials: GE
authors.lastname: Sandusky
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Shoji
authors.initials: S
authors.lastname: Ichikawa
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Imel
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.|Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Chirgwin
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D018920:Coculture Techniques; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000090265:Klotho Proteins; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008875:Middle Aged; D009101:Multiple Myeloma / Q000097:blood / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D010671:Phenylurea Compounds / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D053245:RANK Ligand / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D012886:Skull / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D059016:Tumor Microenvironment; D015854:Up-Regulation; D000099175:Heparanase
chemical_list: D051766:Early Growth Response Protein 1; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors; D005966:Glucuronidase; D000090265:Klotho Proteins; D010671:Phenylurea Compounds; D011743:Pyrimidines; D053245:RANK Ligand; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D000099175:Heparanase; C497325:EGR1 protein, human; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; C505688:TNFSF11 protein, human; C568950:infigratinib
keywords: FGF receptor; FGF23; klotho; multiple myeloma; osteocytes