title: Pregnancy-associated plasma protein-A increases osteoblast proliferation in vitro and bone formation in vivo.
abstract: Pregnancy-associated plasma protein (PAPP)-A, a protease for IGF binding protein (IGFBP)-2, -4, and -5, may enhance IGF action by increasing its bioavailability. Here we have determined the role and mechanism of action of PAPP-A in the regulation of osteoblast proliferation in vitro and bone metabolism in vivo. Recombinant PAPP-A (100 ng/ml) significantly increased osteoblast proliferation and free IGF-I concentration. These effects were abolished by noncleavable IGFBP-4, suggesting that PAPP-A promotes osteoblast proliferation by increasing IGF bioavailability. To determine whether PAPP-A exerts an anabolic effect on bone in vivo, we developed transgenic mice that overexpress PAPP-A in osteoblasts using the 2.3-kb rat type I collagen promoter. Consistent with the increase in IGFBP-4 proteolysis, free IGF-I concentration was significantly increased in the conditioned medium of cultured osteoblasts derived from transgenic mice compared with the wild-type littermates. Calvarial bone thickness, bone marrow cavity, and skull bone mineral density were significantly increased in transgenic mice. Bone size-related parameters in femur and tibia such as total bone area and periosteal circumference as determined by peripheral quantitated computed tomography and histological analysis were significantly increased in transgenic mice. Bone formation rate and osteoid surface were increased by more than 2-fold, whereas bone resorbing surface was unaffected. These anabolic effects were sustained with aging. These findings provide strong evidence that PAPP-A acts as a potent anabolic factor in the regulation of bone formation. Thus, enhancing IGF bioavailability by PAPP-A can be a powerful strategy in the treatment of certain metabolic diseases such as osteoporosis.
authors.affiliation: Musculoskeletal Disease Center, J. L. Pettis Veterans Affairs Medical Center (151), 11201 Benton Street, and Department of Medicine, Loma Linda University, California 92357, USA. Xuezhong.Qin@med.va.gov
authors.forename: Xuezhong
authors.initials: X
authors.lastname: Qin
authors.forename: Jon E
authors.initials: JE
authors.lastname: Wergedal
authors.forename: Mark
authors.initials: M
authors.lastname: Rehage
authors.forename: Kiet
authors.initials: K
authors.lastname: Tran
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Newton
authors.forename: Paggie
authors.initials: P
authors.lastname: Lam
authors.forename: David J
authors.initials: DJ
authors.lastname: Baylink
authors.forename: Subburaman
authors.initials: S
authors.lastname: Mohan
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development; D001682:Biological Availability; D001842:Bone and Bones / Q000033:anatomy & histology; D049109:Cell Proliferation; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000737:chemistry; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009929:Organ Size; D010006:Osteoblasts / Q000166:cytology*; D010012:Osteogenesis / Q000502:physiology*; D011266:Pregnancy-Associated Plasma Protein-A / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013002:Somatomedins / Q000493:pharmacokinetics / Q000502:physiology
chemical_list: D017077:Culture Media, Conditioned; D013002:Somatomedins; D011266:Pregnancy-Associated Plasma Protein-A