TP508 accelerates fracture repair by promoting cell growth over cell death.
ABSTRACT TP508 is a synthetic 23-amino acid peptide representing a receptor-binding domain of human thrombin. We have previously shown that a single injection of TP508 accelerates fracture healing in a rat femoral fracture model. To understand how TP508 acts at the protein level during fracture healing, we compared the translational profiles between saline-control and fractured femur at six time points after TP508 treatment using the second generation of BD Clontechtrade mark Antibody Microarray. Here, we demonstrate that TP508 accelerates fracture healing by modulating expression levels of proteins primarily involved in the functional categories of cell cycle, cellular growth and proliferation, and cell death. The majority of those proteins are physically interrelated and functionally overlapped. The action of those proteins is highlighted by a central theme of promoting cell growth via balance of cell survival over cell death signals. This appears to occur through the stimulation of several bone healing pathways including cell cycle-G1/S checkpoint regulation, apoptosis, JAK/STAT, NF-kappaB, PDGF, PI3K/AKT, PTEN, and ERK/MAPK.
- Journal of Bone and Joint Surgery - British Volume 07/2006; 88(6):701-5. · 2.69 Impact Factor
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ABSTRACT: Thrombin is an essential factor in hemostasis, inflammation, and tissue repair. The synthetic thrombin peptide, TP508, binds to high-affinity thrombin receptors and mimics cellular effects of thrombin at sites of tissue injury. Treatment of full-thickness excisional wounds in normal rats with a single topical application of 0.1 microg TP508 (14 pmol/cm2) reproducibly accelerates wound closure, yielding wounds that on average close 39% more than controls by day 7 (p < 0.001). Wounds treated with 1.0 microg TP508 are 35% and 43% (p < 0.001) smaller than controls on day 7 and 10, respectively. The early rate of closure is approximately 40% greater in TP508-treated than vehicle-treated wounds (20 versus 14 mm2/day) and remains higher through day 7. Breaking strength after closure is slightly greater (15-23%) in wounds treated with TP508 than with saline alone. Histologic comparisons show that TP508 enhances recruitment of inflammatory cells to the wound site within 24 hours post-injury. TP508 treatment also augments revascularization of injured tissue, as evidenced at day 7 by the larger size of functional vessels in the granulation tissue and by the directed development of blood vessels to wounds. These studies raise the possibility that TP508 may be clinically useful in management of open wounds.Wound Repair and Regeneration 01/2000; 8(3):204-15. · 2.76 Impact Factor
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ABSTRACT: The thrombin-related peptide, TP508, has been shown to promote soft tissue healing and fracture repair. One possible clinical application of TP508 is to accelerate bone regeneration during distraction osteogenesis, which is a lengthy procedure involving significant complications. In this study, we tested the ability of TP508 to accelerate the consolidation phase of distraction osteogenesis in a rabbit model of leg lengthening. Twenty-three rabbits had left tibiae lengthened for 1 cm over a period of 6 days. TP 508 (0, 30 and 300 microg in 300 microl saline) was injected into the distraction gaps at the beginning and the end of the lengthening phase, and all the animals were killed 2 weeks after lengthening. By the end of experiment, more animals in the TP508 treated groups had complete bony union of the distraction gaps when compared to the saline treated group. pQCT examination of the regenerates demonstrated a significantly greater bone mineral density (BMD) in the TP508 treated groups relative to the saline control group, but no statistical difference in the BMD was found between the two dosages of TP508. Bone consolidation and bone remodeling was far advanced in the TP508 300 microg treated group, and the regenerates mainly consisted of well-vascularized woven bone. In contrast, in the group that received the 30 microg TP508 treatment, focal bone defects and discontinuities of the new cortices were evident in some but not all animals. In the saline control group a majority of the animals showed large amounts of fibrous and cartilaginous tissues in the regenerates, and none of the regenerates had completed consolidation. This study has demonstrated that local application of TP508 enhanced bone formation and consolidation during distraction osteogenesis in the rabbit. The findings indicate that TP508 may be useful in promoting osteogenesis in situations when augmentative treatment for bone formation and consolidation are needed.Journal of Orthopaedic Research 02/2005; 23(1):196-202. · 2.88 Impact Factor