Local low-dose lovastatin delivery improves the bone-healing defect caused by Nf1 loss of function in osteoblasts

Weixi Wang, Jeffry S. Nyman, Heather E. Moss, Gloria Gutierrez, Gregory R. Mundy, Xiangli Yang, Florent Elefteriou

Research output: Contribution to journalArticlepeer-review

43 Scopus citations


Postfracture tibial nonunion (pseudoarthrosis) leads to lifelong disability in patients with neurofibromatosis type I (NF1), a disorder caused by mutations in the NF1 gene. To determine the contribution of NF1 in bone healing, we assessed bone healing in the Nf1ob-/- conditional mouse model lacking Nf1 specifically in osteoblasts. A closed distal tibia fracture protocol and a longitudinal study design were used. During the 21- to 28-day postfracture period, callus volume, as expected, decreased in wild-type but not in Nf1ob-/- mice, suggesting delayed healing. At these two time points, bone volume (BV/TV) and volumetric bone mineral density (vBMD) measured by 3D micro-computed tomography were decreased in Nf1ob -/- callus-bridging cortices and trabecular compartments compared with wild-type controls. Histomorphometric analyses revealed the presence of cartilaginous remnants, a high amount of osteoid, and increased osteoclast surfaces in Nf1ob-/- calluses 21 days after fracture, which was accompanied by increased expression of osteopontin, Rankl, and Tgfβ. Callus strength measured by three-point bending 28 days after fracture was reduced in Nf1ob-/- versus wild-type calluses. Importantly, from a clinical point of view, this defect of callus maturation and strength could be ameliorated by local delivery of low-dose lovastatin microparticles, which successfully decreased osteoid volume and cartilaginous remnant number and increased callus BV/TV and strength in mutant mice. These results thus indicate that the dysfunctions caused by loss of Nf1 in osteoblasts impair callus maturation and weaken callus mechanical properties and suggest that local delivery of low-dose lovastatin may improve bone healing in NF1 patients.

Original languageEnglish (US)
Pages (from-to)1658-1667
Number of pages10
JournalJournal of Bone and Mineral Research
Issue number7
StatePublished - Jul 2010
Externally publishedYes


  • μCT
  • Fracture
  • Healing
  • Lovastatin
  • Neurofibromatosis type I
  • Nf1
  • Pseudoarthrosis

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine


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