Pregnancy associated plasma protein-A is necessary for expeditious fracture healing in mice

Bradley S. Miller, James T. Bronk, Takayuki Nishiyama, Hiroshi Yamagiwa, Alok Srivastava, Mark E. Bolander, Cheryl A Conover

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)505-513
Number of pages9
JournalJournal of Endocrinology
Volume192
Issue number3
DOIs
StatePublished - Mar 2007

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Pregnancy-Associated Plasma Protein-A
Fracture Healing
Insulin-Like Growth Factor Binding Protein 4
Bony Callus
Knockout Mice
Osteogenesis
Femur
Peptide Hydrolases
Phosphorylation
Fracture Fixation
Metalloproteases
Biological Availability
Cartilage
Histology

ASJC Scopus subject areas

  • Endocrinology

Cite this

Miller, B. S., Bronk, J. T., Nishiyama, T., Yamagiwa, H., Srivastava, A., Bolander, M. E., & Conover, C. A. (2007). Pregnancy associated plasma protein-A is necessary for expeditious fracture healing in mice. Journal of Endocrinology, 192(3), 505-513. https://doi.org/10.1677/JOE-06-0011

Pregnancy associated plasma protein-A is necessary for expeditious fracture healing in mice. / Miller, Bradley S.; Bronk, James T.; Nishiyama, Takayuki; Yamagiwa, Hiroshi; Srivastava, Alok; Bolander, Mark E.; Conover, Cheryl A.

In: Journal of Endocrinology, Vol. 192, No. 3, 03.2007, p. 505-513.

Research output: Contribution to journalArticle

Miller, BS, Bronk, JT, Nishiyama, T, Yamagiwa, H, Srivastava, A, Bolander, ME & Conover, CA 2007, 'Pregnancy associated plasma protein-A is necessary for expeditious fracture healing in mice', Journal of Endocrinology, vol. 192, no. 3, pp. 505-513. https://doi.org/10.1677/JOE-06-0011
Miller BS, Bronk JT, Nishiyama T, Yamagiwa H, Srivastava A, Bolander ME et al. Pregnancy associated plasma protein-A is necessary for expeditious fracture healing in mice. Journal of Endocrinology. 2007 Mar;192(3):505-513. https://doi.org/10.1677/JOE-06-0011
Miller, Bradley S. ; Bronk, James T. ; Nishiyama, Takayuki ; Yamagiwa, Hiroshi ; Srivastava, Alok ; Bolander, Mark E. ; Conover, Cheryl A. / Pregnancy associated plasma protein-A is necessary for expeditious fracture healing in mice. In: Journal of Endocrinology. 2007 ; Vol. 192, No. 3. pp. 505-513.
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