title: Enhancement of fracture healing in the rat, modulated by compounds that stimulate inducible nitric oxide synthase: Acceleration of fracture healing via inducible nitric oxide synthase.
abstract: OBJECTIVE
  We investigated the effects on fracture healing of two up-regulators of inducible nitric oxide synthase (iNOS) in a rat model of an open femoral osteotomy: tadalafil, a phosphodiesterase inhibitor, and the recently reported nutraceutical, COMB-4 (consisting of L-citrulline, Paullinia cupana, ginger and muira puama), given orally for either 14 or 42 days.
  
  
  METHODS
  Unilateral femoral osteotomies were created in 58 male rats and fixed with an intramedullary compression nail. Rats were treated daily either with vehicle, tadalafil or COMB-4. Biomechanical testing of the healed fracture was performed on day 42. The volume, mineral content and bone density of the callus were measured by quantitative CT on days 14 and 42. Expression of iNOS was measured by immunohistochemistry.
  
  
  RESULTS
  When compared with the control group, the COMB-4 group exhibited 46% higher maximum strength (t-test, p = 0.029) and 92% higher stiffness (t-test, p = 0.023), but no significant changes were observed in the tadalafil group. At days 14 and 42, there was no significant difference between the three groups with respect to callus volume, mineral content and bone density. Expression of iNOS at day 14 was significantly higher in the COMB-4 group which, as expected, had returned to baseline levels at day 42.
  
  
  CONCLUSIONS
  This study demonstrates an enhancement in fracture healing by an oral natural product known to augment iNOS expression.Cite this article:R. A. Rajfer, A. Kilic, A. S. Neviaser, L. M. Schulte, S. M. Hlaing, J. Landeros, M. G. Ferrini, E. Ebramzadeh, S-H. Park. Enhancement of fracture healing in the rat, modulated by compounds that stimulate inducible nitric oxide synthase: Acceleration of fracture healing via inducible nitric oxide synthase.Bone Joint Res2017:6:-97. DOI: 10.1302/2046-3758.62.BJR-2016-0164.R2.
authors.affiliation: Department of Orthopaedic Surgery, George Washington University, Washington DC, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Rajfer
authors.affiliation: Department of Orthopaedics, School of Medicine, Bahcesehir University, Istanbul, Turkey.
authors.forename: A
authors.initials: A
authors.lastname: Kilic
authors.affiliation: Department of Orthopaedic Surgery, George Washington University, Washington DC, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Neviaser
authors.affiliation: Department of Orthopaedic Surgery, George Washington University, Washington DC, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Schulte
authors.affiliation: Department of Health and Life Sciences, College of Science and Health, Charles Drew University of Medicine and Science, Los Angeles, California, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Hlaing
authors.affiliation: Department of Health and Life Sciences, College of Science and Health, Charles Drew University of Medicine and Science, Los Angeles, California, USA.
authors.forename: J
authors.initials: J
authors.lastname: Landeros
authors.affiliation: Department of Health and Life Sciences, College of Science and Health, Charles Drew University of Medicine and Science, Los Angeles, California, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Ferrini
authors.affiliation: Department of Orthopaedic Surgery, The J. Vernon Luck, Sr., M.D. Orthopaedic Research Center, Orthopaedic Institute for Children, University of California, Los Angeles, California, USA.
authors.forename: E
authors.initials: E
authors.lastname: Ebramzadeh
authors.affiliation: Department of Orthopaedic Surgery, The J. Vernon Luck, Sr., M.D. Orthopaedic Research Center, Orthopaedic Institute for Children, University of California, Los Angeles, California, USA SangHyunPark@mednet.ucla.edu.
authors.forename: S-H
authors.initials: SH
authors.lastname: Park
keywords: Biomechanical; Fracture; Inducible nitric oxide synthase; Nutraceutical; Tadalafil