Pregnancy associated plasma protein-A is necessary for expeditious fracture healing in mice.
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.
Miller
Bradley S
BS
Endocrine Research Unit, Mayo Clinic, 200 First, Street SW, 5-194 Joseph, Rochester, Minnesota 55905, USA.
Bronk
James T
JT
Nishiyama
Takayuki
T
Yamagiwa
Hiroshi
H
Srivastava
Alok
A
Bolander
Mark E
ME
Conover
Cheryl A
CA
D000818:Animals; D001696:Biomechanical Phenomena; D002146:Bony Callus / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D005260:Female; D005264:Femoral Fractures / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D017102:Fracture Healing; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011266:Pregnancy-Associated Plasma Protein-A / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011859:Radiography; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D013997:Time Factors
D017526:Receptor, IGF Type 1; D011266:Pregnancy-Associated Plasma Protein-A