Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15240, USA.
J Biol Chem. 2012 Jun 15;287(25):21450-60. doi: 10.1074/jbc.M111.331249. Epub 2012 May 3.
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.
骨骼重塑是一个复杂的过程，必须精确控制以维持健康的生活。我们在这里展示，细丝结合 LIM 蛋白 1（FBLP-1，也称为 migfilin），一种连接蛋白和细丝的黏着斑蛋白，对于适当控制骨骼重塑是必不可少的。在小鼠中基因敲除 FBLIM1（编码 FBLP-1 的基因）导致严重的骨质疏松表型。与野生型 BMSCs 相比，FBLP-1 缺失的原代 BMSCs 的细胞外基质黏附和迁移能力显著降低。FBLP-1 的缺失显著损害了 BMSCs 在体外的生长和存活，并减少了骨髓中的成骨细胞（OB）祖细胞数量和体内的 OB 分化。此外，FBLP-1 的缺失导致体内破骨细胞（OCL）分化显著增加。核因子κB 配体（RANKL）的水平，OCL 分化的关键调节剂，在 FBLP-1 缺失的 BMSCs 中明显增加。然而，FBLP-1 缺失的骨髓单核细胞（BMMs）在外源供应的 RANKL 刺激下分化为多核 OCL 的能力与 WT BMMs 没有不同。最后，我们表明 FBLP-1 的缺失促进了 ERK1/2 的激活磷酸化。ERK1/2 激活的抑制显著抑制了由 FBLP-1 缺失引起的 RANKL 诱导的增加。我们的结果将 FBLP-1 确定为骨稳态的关键调节剂，并表明 FBLP-1 通过调节 OB/BMSCs 的内在特性（即 BMSC-细胞外基质黏附和迁移、细胞生长、存活和分化）以及 OB/BMSCs 和 BMMs 之间的通讯（即 RANKL 表达）来发挥作用，从而控制破骨细胞生成。
