title: Critical role of filamin-binding LIM protein 1 (FBLP-1)/migfilin in regulation of bone remodeling.
abstract: Bone remodeling is a complex process that must be precisely controlled to maintain a healthy life. We show here that filamin-binding LIM protein 1 (FBLP-1, also known as migfilin), a kindlin- and filamin-binding focal adhesion protein, is essential for proper control of bone remodeling. Genetic inactivation of FBLIM1 (the gene encoding FBLP-1) in mice resulted in a severe osteopenic phenotype. Primary FBLP-1 null bone marrow stromal cells (BMSCs) exhibited significantly reduced extracellular matrix adhesion and migration compared with wild type BMSCs. Loss of FBLP-1 significantly impaired the growth and survival of BMSCs in vitro and decreased the number of osteoblast (OB) progenitors in bone marrow and OB differentiation in vivo. Furthermore, the loss of FBLP-1 caused a dramatic increase of osteoclast (OCL) differentiation in vivo. The level of receptor activator of nuclear factor κB ligand (RANKL), a key regulator of OCL differentiation, was markedly increased in FBLP-1 null BMSCs. The capacity of FBLP-1 null bone marrow monocytes (BMMs) to differentiate into multinucleated OCLs in response to exogenously supplied RANKL, however, was not different from that of WT BMMs. Finally, we show that a loss of FBLP-1 promotes activating phosphorylation of ERK1/2. Inhibition of ERK1/2 activation substantially suppressed the increase of RANKL induced by the loss of FBLP-1. Our results identify FBLP-1 as a key regulator of bone homeostasis and suggest that FBLP-1 functions in this process through modulating both the intrinsic properties of OB/BMSCs (i.e., BMSC-extracellular matrix adhesion and migration, cell growth, survival, and differentiation) and the communication between OB/BMSCs and BMMs (i.e., RANKL expression) that controls osteoclastogenesis.
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15240, USA. xiaogz118@gmail.com
authors.forename: Guozhi
authors.initials: G
authors.lastname: Xiao
authors.forename: Hongqiang
authors.initials: H
authors.lastname: Cheng
authors.forename: Huiling
authors.initials: H
authors.lastname: Cao
authors.forename: Ka
authors.initials: K
authors.lastname: Chen
authors.forename: Yizeng
authors.initials: Y
authors.lastname: Tu
authors.forename: Shibing
authors.initials: S
authors.lastname: Yu
authors.forename: Hongli
authors.initials: H
authors.lastname: Jiao
authors.forename: Shengyong
authors.initials: S
authors.lastname: Yang
authors.forename: Hee-Jeong
authors.initials: HJ
authors.lastname: Im
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.forename: Chuanyue
authors.initials: C
authors.lastname: Wu
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D016723:Bone Remodeling / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D048052:Mitogen-Activated Protein Kinase 3