title: Activated protein C (APC) can increase bone anabolism via a protease-activated receptor (PAR)1/2 dependent mechanism.
abstract: Activated Protein C (APC) is an anticoagulant with strong cytoprotective properties that has been shown to promote wound healing. In this study APC was investigated for its potential orthopedic application using a Bone Morphogenetic Protein 2 (rhBMP-2) induced ectopic bone formation model. Local co-administration of 10 µg rhBMP-2 with 10 µg or 25 µg APC increased bone volume at 3 weeks by 32% (N.S.) and 74% (p<0.01) compared to rhBMP-2 alone. This was associated with a significant increase in CD31+ and TRAP+ cells in tissue sections of ectopic bone, consistent with enhanced vascularity and bone turnover. The actions of APC are largely mediated by its receptors endothelial protein C receptor (EPCR) and protease-activated receptors (PARs). Cultured pre-osteoblasts and bone nodule tissue sections were shown to express PAR1/2 and EPCR. When pre-osteoblasts were treated with APC, cell viability and phosphorylation of ERK1/2, Akt, and p38 were increased. Inhibition with PAR1 and sometimes PAR2 antagonists, but not with EPCR blocking antibodies, ameliorated the effects of APC on cell viability and kinase phosphorylation. These data indicate that APC can affect osteoblast viability and signaling, and may have in vivo applications with rhBMP-2 for bone repair.
authors.affiliation: Sutton Arthritis Research Laboratory, Kolling Institute at Royal North Shore Hospital, Sydney, Australia.
authors.forename: Kaitlin
authors.initials: K
authors.lastname: Shen
authors.forename: Ciara M
authors.initials: CM
authors.lastname: Murphy
authors.forename: Ben
authors.initials: B
authors.lastname: Chan
authors.forename: Mille
authors.initials: M
authors.lastname: Kolind
authors.forename: Tegan L
authors.initials: TL
authors.lastname: Cheng
authors.forename: Kathy
authors.initials: K
authors.lastname: Mikulec
authors.forename: Lauren
authors.initials: L
authors.lastname: Peacock
authors.forename: Meilang
authors.initials: M
authors.lastname: Xue
authors.forename: Sang-Youel
authors.initials: SY
authors.lastname: Park
authors.forename: David G
authors.initials: DG
authors.lastname: Little
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Jackson
authors.forename: Aaron
authors.initials: A
authors.lastname: Schindeler
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology; D001862:Bone Resorption / Q000517:prevention & control; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D011486:Protein C / Q000378:metabolism / Q000494:pharmacology*; D044463:Receptor, PAR-1 / Q000502:physiology*; D044464:Receptor, PAR-2 / Q000502:physiology*
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D011486:Protein C; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2
keywords: APC; PAR1/2; activated protein C; bone anabolism; rhBMP-2 induced bone