title: Impact of pregnancy-associated plasma protein-a deletion on the adult murine skeleton.
abstract: BACKGROUND
  The metalloproteinase, pregnancy-associated plasma protein-A (PAPP-A) functions to enhance local insulin-like growth factor (IGF)-I bioavailability through cleavage of inhibitory IGF binding proteins. Because IGF-I is an important regulator of skeletal growth and remodeling and PAPP-A is highly expressed by osteoblastic cells, we hypothesized that, in the absence of PAPP-A, bone physiology would be compromised because of a blunting of local IGF-I action even in the presence of normal circulating IGF-I levels.
  
  
  METHODS
  pQCT, muCT, histomorphometry, and mechanical strength testing were performed on bones from PAPP-A knockout (KO) mice and wildtype (WT) littermates at 2-12 mo of age. IGF-I levels and bone formation and resorption markers were determined in sera from these animals.
  
  
  RESULTS
  Volumetric BMD in PAPP-A KO mice measured by pQCT at the femoral midshaft, which is primarily cortical bone, was 10% less than WT at 2 mo. This difference was maintained at 4, 6, and 12 mo. Cortical thickness at this site was similarly decreased. On the other hand, trabecular bone at the distal femur (pQCT) and in the tibia (muCT) showed age-progressive decreases in bone volume fraction in PAPP-A KO compared with WT mice. Tibial muCT indicated a 46% relative decrease in trabecular bone volume/total volume (BV/TV) and a 28% relative decrease in trabecular thickness in PAPP-A KO compared with WT mice at 6 mo. These trabecular deficiencies in PAPP-A KO mice corresponded to a weakening of the bone. Serum markers and bone histomorphometry indicated that the primary impact of PAPP-A is on skeletal remodeling resulting in a state of low-turnover osteopenia in adult PAPP-A KO mice. Circulating IGF-I levels were not altered in PAPP-A KO mice.
  
  
  CONCLUSIONS
  PAPP-A is a bone growth regulatory factor in vivo and, in its absence, mice show skeletal insufficiency in mass, density, architecture, and strength. The data suggest a primary role for PAPP-A in modulating local IGF bioavailability for trabecular bone remodeling.
authors: Endocrine Research Unit, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors: Sharon J
authors: SJ
authors: Tanner
authors: Theresa E
authors: TE
authors: Hefferan
authors: Clifford J
authors: CJ
authors: Rosen
authors: Cheryl A
authors: CA
authors: Conover
mesh_terms: D000818:Animals; D015519:Bone Density; D001842:Bone and Bones / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D011257:Pregnancy Proteins / Q000235:genetics* / Q000502:physiology; D014057:Tomography, X-Ray Computed
chemical_list: D011257:Pregnancy Proteins