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NF1 Gene Expression in Mouse Fracture Healing and in Experimental Rat Pseudarthrosis

Tommi Kuorilehto, Erika Ekholm, Marja Nissinen, Kalevi Hietaniemi, Ari Hiltunen, Pekka Paavolainen, Risto Penttinen and Juha Peltonen

Department of Anatomy and Cell Biology (TK,MN,JP) and Department of Dermatology (JP), University of Oulu, Oulu, Finland; Department of Anatomy, Institute of Biomedicine (TK,JP), Department of Medical Biochemistry (EE,RP), and Department of Surgery (AH), University of Turku, Turku, Finland; Department of Orthopaedics and Traumatology, Helsinki University Central Hospital, Jorvi Hospital, Espoo, Finland (KH); and ORTON Orthopaedic Hospital of Invalid Foundation, Helsinki, Finland (PP)

Correspondence to: Dr. Juha Peltonen, Department of Anatomy, Institute of Biomedicine, University of Turku, Kiinanmyllynkatu 10, FIN-20520 Turku, Finland. E-mail: juha.peltonen{at}utu.fi

Neurofibromatosis type 1 (NF1) is an inherited disease with an incidence of about 1:3000 worldwide. Approximately half of all patients with NF1 present osseous manifestations, which can vary from mild to severely debilitating changes such as congenital pseudarthrosis. In the present study, fracture healing of mouse tibia was followed and specimens were collected 5, 9, 14, and 22 days postoperatively. Experimental pseudarthrosis of rat was followed up to 15 weeks postoperatively. In situ hybridization and immunohistochemistry were used to demonstrate expression of NF1 tumor suppressor and phosphorylated p44/42 mitogen-activated protein kinase (MAPK), an indicator of the Ras-MAPK pathway. The results showed that ossified callus was formed in mouse fracture 22 days after the operation. The final outcome of rat pseudarthrosis was detected 9 weeks after the operation, presenting abundant cartilaginous callus at the pseudarthrosis. NF1 gene expression was noted in the maturing and in the hypertrophic cartilages during normal mouse fracture healing, and in rat pseudarthrosis. Phosphorylated p44/42 MAPK was detected in a subpopulation of the hypertrophic chondrocytes in both models. Furthermore, positive labeling for NF1 mRNA and protein was detected in endothelium in both the pseudarthrosis and in the fracture. In conclusion, NF1 gene expression and function are needed for normal fracture healing, possibly restraining excessive Ras-MAPK pathway activation. (J Histochem Cytochem 54:363–370, 2006)

Key Words: neurofibromatosis type 1 • fracture • pseudarthrosis • Ras • neurofibromin

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