von Willebrand factor (vWF) is a multimeric plasma protein with ABO (H) blood group sugar chains. We investigated a total of 330 plasmas from normal individuals having various ABO genotypes, with special reference to vWF antigen and its platelet glycoprotein-Ib-related biological activities, termed ristocetin cofactor (RCof) and botrocetin cofactor (BCof). RCof reflects the biological activity of higher vWF multimers, while BCof reflects that of vWF of multimers of all sizes. Plasmas from normal individuals carrying one O gene (genotypes AO and BO) had slightly, but proportionally lower levels of vWF antigen, RCof, and BCof than those carrying no O gene (genotypes AA, AB, and BB). Normal plasmas from individuals carrying two O genes (genotype OO) showed much lower values for these parameters than the other plasmas, as previously reported. However, multimeric analysis of plasma vWF antigen revealed no differences among the different genotypes.

Pregnancy-associated plasma protein A (PAPP-A), a metalloproteinase that regulates IGF bioavailability in vitro through cleavage of inhibitory IGF-binding protein-4 (IGFBP-4), has been implicated in skeletal development and injury repair responses. However, direct in vivo data are lacking. In this study, we used PAPP-A knock-out (KO) mice to determine the role of PAPP-A in fracture repair. Stabilized mid-shaft fractures were produced in femurs of 3-month-old mice. At 14 days post-fracture, complete bony bridging of the fracture callus was seen radiographically in wild-type but not in PAPP-A KO mice. Histological examination 5 to 28 days post-fracture showed reductions in the amount of intramembranous bone formation, cartilage production, endochondral ossification and remodeling in PAPP-A KO compared with wild-type mice. However, fracture healing appeared similar in both groups at 42 days post-fracture when analyzed by histology. A similar degree of healing strength in wild-type and PAPP-A KO femurs was demonstrated by mechanical testing at 28 and 42 days post-fracture. Untreated cultures of day 5 fracture calluses from wild-type mice showed robust IGFBP-4 protease activity and IGF receptor phosphorylation, whereas fracture calluses from PAPP-A KO mice had no IGFBP-4 protease activity and reduced IGF receptor phosphorylation. These data demonstrate a marked delay in fracture healing in PAPP-A KO compared with wild-type mice, and suggest that PAPP-A is necessary in the early phases of the process for expeditious fracture repair. The ability of PAPP-A to enhance local IGF action may be an important mechanism for optimizing the fracture repair response.

No abstract

No abstract