Table 1: Therapeutic approaches in NF1 patients and disease mouse models.
Therapeutic approach Model system Addressed molecular pathway and outcome Reference
systemic oral application of MEK inhibitor PD198306 (20 mg/kg/day) for 5 weeks starting with 4 weeks of age Col1a1Cre;Nf1flox/flox permanent knockout in osteoblast progenitors; no fracture normalization of MAPK/MEK signaling reduces hyperosteoidosis [29]
no intervention fracture model of Nf1+/- diaphyseal and distal tibia delayed fracture healing of distal tibia due to delayed cartilage removal, fibrous tissue accumulation, insufficient bone formation [42]
intramuscular BMP-2 (20 mg) + systemic zoledronic acid (0.02 mg/kg) twice a week intramuscular induction of heterotopic bone in Nf1+/- quadriceps BMP-2 induced less heterotopic bone in Nf1+/-mice, combined treatment of zoledronic acid with BMP-2 synergistically increased heterotopic bone [46]
no intervention defect model in tibia cortex of Prx1Cre;Nf1flox/flox mice delayed cortical boned efect healing due to accumulation/persistence of fibrocartilaginous tissue and delayed bone formation [3]
systemic lovastatin application (daily oral gavage 0.15 mg activated lovastatin) defect model in tibia cortex of Prx1Cre;Nf1flox/flox mice inhibition of Ras/MAPK/MEK signaling with lovastatin normalized delayed fracture healing in Prx1Cre;Nf1flox/flox mice [3]
single local low-dose lovastatin delivery via microparticles (10 mg/kg) tibia fracture model of 2 month Col1a1Cre;Nf1flox/flox mice localized inhibition of MAPK/ERK signaling decreased osteoid volume and increased callus bone mass in Col1a1;Nf1flox/flox mice [33]
surgery of congenital tibia pseudarthrosis followed by BMP-7 (OP-1) administration and pamidronate or zoledronic acid application 7 patients with congenital pseudarthrosis of the tibia (6 patients diagnosed as NF1), median age 7 years 6 patients healed to primary healing within 5.5 month
BMP-7 and bisphosphonates support fracture healing after pseudarthrosis surgery in NF1 patients		 [50]
no intervention open and closed tibia fracture model of AdenoCre;Nf1flox/- and AdenoCre;Nf1flox/flox mice closed fracture: strongly reduced fracture union rates, increase of non-bony/fibrous tissues in callus, increased cell proliferation in callus, increased osteoclasts
open fracture: strongly reduced fracture union rates, increase of non-bony/fibrous tissues in callus, mild increase in cell proliferation in callus, massive increase in osteoclasts		 [47]
constant subcutaneous administration (osmotic pump) of PD98059 (10 mg/kg/day) tibia fracture model of Col1a1Cre;Nf1flox/- mice inhibition of MEK signaling with PD98059 normalizes Erk activation and promotes Ob differentation; PD98059 normalizes Oc differentiation [44]
individual or combined administration of rhBMP-2 (10 μg) and the MEK inhibitor PD0325901(10 mg/kg/day from two days before fracture to ten days after fracture) tibia mid shaft fracture model of AdenoCre;Nf1flox/-and AdenoCre;Nf1flox/flox mice
closed and open fracture model		 results: delivery vehicle alone, PD0325901, rhBMP-2, or PD0325901+rhBMP-2 gave fracture union rates of 0%, 8%, 69% (p < 0.01), or 80% (p < 0.01), respectively PD0325901+rhBMP-2 induces increased callus size but did not reduce fibrotic tissue accumulation [41]
local rhBMP-7 treatment after pseudarthrosis surgery randomized study of 20 patients associated with NF1 to test beneficial impact of BMP-7 after surgery, Kirschner fixation, autologous bone grafting no difference in healing time between BMP-7 and control group
no pre- to post-operative improvement between BMP-7 and control group		 [52]
rhBMP-2 (5 mg) loaded on collagen sponges
zoledronic acid was given at 0.02 mg/kg (total dose 0.1 mg/kg) by biweekly subcutaneous injection starting 3 days postoperatively		 posterolateral fusion model of lumbar spine L4 to L6 in Nf1+/- mice combined rhBMP-2 and zoledronic acid treatment maximized bone formation by diminishing osteoclast numbers [48]
systemic treatment with sALP-FcD10 (bone targeted alkaline phosphatase) of newborn mice (8.2 mg/kg/day for 18 days) Col2a1Cre;Nf1flox/flox
permanent knock-out in chondrogenic progenitors;
no fracture		 normalization of mineralization by degradation of accumulating PPi
partial rescue of growth retardation, cortical thickness, cortical geometry, mineral density		 [32]
systemic treatment with sALP-FcD10(bone targeted alkaline phosphatase) from P14 for 6 weeks) (8.2 mg/kg/day for 18 days) inducible Tet-Off-based OsxCre;Nf1flox/flox repression of Nf1 knock-out from conception to postnatal day 14
no fracture		 normalization of mineralization by degradation of accumulating PPi
rescue of trabecular bone mass, hyperosteoidosis, bone mineral density, mechanical parameter		 [32]
independent or combined treatment with 20 μl rBMP2-polygycidol (0.50 μg/μl) or 20 μl Trametinib nanoparticles (MEK inhibitor, 0.188 μg/μl) at day 1 and 7 post-fracture, analysis 21 days post-fracture inducible Tet-Off-based OsxCre;Nf1flox/flox repression of Nf1 knock-out from conception to postnatal day 14 mid-diaphyseal tibia fracture of 2 month mice, intramedullary fixation Tet-Off-based OsxCre;Nf1flox/flox mice treated with doxycycline develop normally but demonstrate defective fracture healing only combined treatment with rBMP2-polygycidol and Trametinib normalized fracture healing [49]
treatment with rhBMP-2 and intramedullary fixation in NF1 patients with congenital tibia pseudarthrosis 15 NF1 patients with congenital tibia pseud-arthrosis nonunion fractures underwent surgery with subsequent rhBMP-2 treatment outcome: 3 patients underwent successful healing with rhBMP-2, 5 patients failed to heal, 3 patients amputated, 5 patients had persistent nonunions, 3 patients refractured
rhBMP-2 may support fracture healing after surgery in NF1 patients		 [51]