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

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.

Lack of Functional Pregnancy-Associated Plasma Protein-A (PAPPA) Compromises Mouse Ovarian Steroidogenesis and Female Fertility1

“…In the PAPP-A KO mouse, in addition to the delay in the switch from E 2 to P 4 production of granulosa after hCG treatment observed herein, delayed development of the fetus, delayed wound healing, and delayed healing of bone fractures have been observed [18,41,42], underscoring a common delay or reduction in IGF-assisted physiological processes in this model. An important pursuit in human ovarian physiology is to determine the function of PAPPA in the corpus luteum and whether there is a role for compromised PAPPA activity in follicles resistant to gonadotropin stimulation and in the setting of compromised corpus luteum production of P 4 in some women with infertility and luteal insufficiency.…”

Placental Regulation of Peptide Hormone and Growth Factor Activity by proMBP1

“…TGFB and the IGFs belong to a subset of growth factors that are stored in the bone matrix and released during osteoclast resorption to mediate local coupling of bone formation and resorption [71]. The role of PAPPA in the formation of new bone has recently been verified in vivo in two studies describing increased osteoblast proliferation in transgenic mice that overexpress PAPPA in osteoblasts [72] and delayed bone fracture repair in Pappa knockout mice [73]. Interestingly, the treatment of fibroblasts and osteoblasts with phorbol ester tumor promoters and their transformation with simian virus 40 large T antigen resulted in inhibition of IGFBP4 proteolytic activity without a reduction in PAPPA expression [74,75].…”

Contrasting bone effects of temporary versus permanent IGFBP administration in rodents

“…The relevance of PAPP-A for bone growth was assessed by gene knockout [27] or overexpression experiments [28], the latter of which displayed marked elevations of bone thickness, mineral density and periosteal circumference. The mechanism of IGF-mobilization by proteolysis of IGFBP-4 seems to be of particular relevance for bone repair since fracture healing was delayed in PAPP-A knockout mice [29].…”