Modeling bone morphogenetic protein and bisphosphonate combination therapy in wild-type and Nf1 haploinsufficient mice.
Recombinant bone morphogenetic proteins (BMPs) show promise in treating the orthopedic complications associated with neurofibromatosis type 1 (NF1), such as congenital pseudarthrosis of the tibia. Minimal scientific information regarding the effects of BMP in the context of NF1 is available. As abnormalities in both bone formation and resorption have been documented in Nf1-deficient mice, we hypothesized that inadequate BMP-induced bone formation could be augmented by cotreatment with the bisphosphonate zoledronic acid (ZA). First, primary osteoblasts isolated from wild type (Nf1(+/+)) and Nf1-deficient (Nf1(+/-)) mice were cultured in the presence and absence of BMP-2. While Nf1(+/-) cells exhibited less osteogenic potential than Nf1(+/+) cells, alkaline phosphatase expression and matrix mineralization for both genotypes were enhanced by BMP-2 treatment. To model this response in vivo, 20 microg BMP-2 was implanted intramuscularly into the quadriceps of mice to induce heterotopic bone. Radiographs revealed significantly less net bone formation in Nf1(+/-) mice compared to Nf1(+/+) controls. To test the effect of an antiresorptive agent, mice were cotreated twice weekly from postoperative day 3 with 0.02 mg/kg ZA or with saline. ZA treatment led to a synergistic increase in the amount of heterotopic bone in both Nf1(+/+) and Nf1(+/-) mice compared with saline controls, as measured by DEXA and histomorphometry. Thus, the anabolic deficiency noted in Nf1(+/-) mice is amenable to stimulation by BMP-2, but mineralized tissue formation remains below that of Nf1(+/+) controls. Bisphosphonate combination therapy is superior to BMP therapy alone in terms of net bone production in vivo in both wild-type and Nf1-deficient mice.
Schindeler
Aaron
A
Department of Orthopaedic Research & Biotechnology, The Children's Hospital at Westmead, Sydney, Australia. AaronS@chw.edu.au
Ramachandran
Manoj
M
Godfrey
Craig
C
Morse
Alyson
A
McDonald
Michelle
M
Mikulec
Kathy
K
Little
David G
DG
D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001851:Bone Diseases, Metabolic / Q000188:drug therapy* / Q000209:etiology; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004164:Diphosphonates / Q000494:pharmacology*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004734:Energy Metabolism; D005260:Female; D005269:Femur / Q000166:cytology; D006239:Haplotypes; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009456:Neurofibromatosis 1 / Q000150:complications*; D025542:Neurofibromin 1 / Q000235:genetics*; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D012886:Skull / Q000166:cytology; D013977:Tibia / Q000166:cytology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D000077211:Zoledronic Acid