title: Pregnancy-associated plasma protein-A modulates the anabolic effects of parathyroid hormone in mouse bone.
abstract: 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 μg/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.
authors: Division of Endocrinology, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905, United States.
authors: Kari B
authors: KB
authors: Clifton
authors: Division of Endocrinology, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905, United States. Electronic address: Conover.Cheryl@mayo.edu.
authors: Cheryl A
authors: CA
authors: Conover
mesh_terms: D015502:Absorptiometry, Photon; D045930:Anabolic Agents / Q000627:therapeutic use; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism*; D003720:Densitometry; D005269:Femur / Q000187:drug effects; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006579:Heterozygote; D006801:Humans; D007279:Injections, Subcutaneous; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008660:Metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000187:drug effects; D010281:Parathyroid Hormone / Q000627:therapeutic use*; D011266:Pregnancy-Associated Plasma Protein-A / Q000378:metabolism*; D013977:Tibia / Q000378:metabolism
chemical_list: D045930:Anabolic Agents; D018974:Insulin-Like Growth Factor Binding Protein 4; D010281:Parathyroid Hormone; D007334:Insulin-Like Growth Factor I; D011266:Pregnancy-Associated Plasma Protein-A
keywords: Insulin-like growth factor; Insulin-like growth factor binding proteins; Parathyroid hormone; Pregnancy-associated plasma protein-A