Pregnancy-associated plasma protein-A modulates the anabolic effects of parathyroid hormone in mouse bone

被引:6
作者
Clifton, Kari B. [1 ]
Conover, Cheryl A. [1 ]
机构
[1] Mayo Clin, Div Endocrinol, Rochester, MN 55905 USA
关键词
Pregnancy-associated plasma protein-A; Parathyroid hormone; Insulin-like growth factor; Insulin-like growth factor binding proteins; GROWTH-FACTOR-I; IGF-I; BINDING-PROTEIN; MICE; RESISTANCE; DELETION; RECEPTOR;
D O I
10.1016/j.bone.2015.08.015
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Intermittent parathyroid hormone (PTH) is a potent anabolic therapy for bone, and several studies have implicated local insulin-like growth factor (IGF) signaling in mediating this effect The IGF system is complex and includes ligands and receptors, as well as IGF binding proteins (IGFBPs) and IGFBP proteases. Pregnancy-associated plasma protein-A (PAPP-A) is a metalloprotease expressed by osteoblasts in vitro that has been shown to enhance local IGF action through cleavage of inhibitory IGFBP-4. This study was set up to test two specific hypotheses: 1) Intermittent PTH treatment increases the expression of IGF-I, IGFBP-4 and PAPP-A in bone in vivo, thereby increasing local IGF activity. 2) In the absence of PAPP-A, local IGF activity and the anabolic effects of PTH on bone are reduced. Wild-type (WT) and PAPP-A knock-out (KO) mice were treated with 80 mu g/kg human PTH 1-34 or vehicle by subcutaneous injection five days per week for six weeks. IGF-I, IGFBP-4 and PAPP-A mRNA expression in bone were significantly increased in response to PTH treatment PTH treatment of WT mice, but not PAPP-A KO mice, significantly increased expression of an IGF-responsive gene. Bone mineral density (BMD), as measured by DEXA, was significantly decreased in femurs of PAPP-A KO compared to WT mice with PTH treatment. Volumetric BMD, as measured by pQCT, was significantly decreased in femoral midshaft (primarily cortical bone), but not metaphysis (primarily trabecular bone), of PAPP-A KO compared to WT mice with PTH treatment These data suggest that stimulation of PAPP-A expression by intermittent PTH treatment contributes to PTH bone anabolism in mice. (C) 2015 Elsevier Inc. All rights reserved.
引用
收藏
页码:413 / 416
页数:4
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