3 research outputs found
Parathyroid hormone stimulates bone regeneration in an atrophic non-union model in aged mice
Background Non-union formation still represents a major burden in trauma and orthopedic surgery. Moreover, aged
patients are at an increased risk for bone healing failure. Parathyroid hormone (PTH) has been shown to accelerate
fracture healing in young adult animals. However, there is no information whether PTH also stimulates bone regeneration in atrophic non-unions in the aged. Therefore, the aim of the present study was to analyze the efect of PTH
on bone regeneration in an atrophic non-union model in aged CD-1 mice.
Methods After creation of a 1.8 mm segmental defect, mice femora were stabilized by pin-clip fxation. The animals
were treated daily with either 200 mg/kg body weight PTH 1–34 (n=17) or saline (control; n=17) subcutaneously.
Bone regeneration was analyzed by means of X-ray, biomechanics, micro-computed tomography (µCT) imaging
as well as histological, immunohistochemical and Western blot analyses.
Results In PTH-treated animals bone formation was markedly improved when compared to controls. This was associated with an increased bending stifness as well as a higher number of tartrate-resistant acid phosphatase (TRAP)-
positive osteoclasts and CD31-positive microvessels within the callus tissue. Furthermore, PTH-treated aged animals showed a decreased infammatory response, characterized by a lower number of MPO-positive granulocytes
and CD68-positive macrophages within the bone defects when compared to controls. Additional Western blot
analyses demonstrated a signifcantly higher expression of cyclooxygenase (COX)-2 and phosphoinositide 3-kinase
(PI3K) in PTH-treated mice.
Conclusion Taken together, these fndings indicate that PTH is an efective pharmacological compound for the treatment of non-union formation in aged animals
Cilostazol promotes blood vessel formation and bone regeneration in a murine non-union model
Non-unions represent a major complication in trauma and orthopedic surgery. Many factors contribute to bone
regeneration, out of which an adequate vascularization has been recognized as crucial. The phosphodiesterase-3
(PDE-3) inhibitor cilostazol has been shown to exert pro-angiogenic and pro-osteogenic effects in a variety of
preclinical studies. Hence, we herein investigated the effects of cilostazol on bone regeneration in an atrophic
non-union model in mice. For this purpose, a 1.8 mm femoral segmental defect was stabilized by pin-clip fixation
and the animals were treated daily with 30 mg/kg body weight cilostazol or saline (control) per os. At 2, 5 and 10
weeks after surgery the healing of femora was analyzed by X-ray, biomechanics, photoacoustic imaging, and
micro-computed tomography (µCT). To investigate the cellular composition and the growth factor expression of
the callus tissue additional histological, immunohistochemical and Western blot analyses were performed.
Cilostazol-treated animals showed increased bone formation within the callus, resulting in an enhanced bending
stiffness when compared to controls. This was associated with a more pronounced expression of vascular
endothelial growth factor (VEGF), a higher number of CD31-positive microvessels and an increased oxygen
saturation within the callus tissue. Furthermore, cilostazol induced higher numbers of tartrate-resistant acidic
phosphate (TRAP)-positive osteoclasts and CD68-positive macrophages. Taken together, these findings demonstrate that cilostazol is a promising drug candidate for the adjuvant treatment of atrophic non-unions in clinical
practice
Sildenafil, a phosphodiesterase-5 inhibitor, stimulates angiogenesis and bone regeneration in an atrophic non-union model in mice
Abstract Non-union formation represents a major complication in trauma and orthopedic surgery. The phosphodiesterase-5 (PDE-5) inhibitor sildenafil has been shown to exert pro-angiogenic and pro-osteogenic effects in vitro and in vivo. Therefore, the aim of the present study was to analyze the impact of sildenafil in an atrophic non-union model in mice. After creation of a 1.8 mm segmental defect, mice femora were stabilized by pin-clip fixation. Bone regeneration was analyzed by means of X-ray, biomechanics, photoacoustic and micro-computed tomography (µCT) imaging as well as histological, immunohistochemical and Western blot analyses at 2, 5 and 10 weeks after surgery. The animals were treated daily with either 5 mg/kg body weight sildenafil (n = 35) or saline (control; n = 35) per os. Bone formation was markedly improved in defects of sildenafil-treated mice when compared to controls. This was associated with a higher bending stiffness as well as an increased number of CD31-positive microvessels and a higher oxygen saturation within the callus tissue. Moreover, the bone defects of sildenafil-treated animals contained more tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts and CD68-positive macrophages and exhibited a higher expression of the pro-angiogenic and pro-osteogenic markers cysteine rich protein (CYR)61 and vascular endothelial growth factor (VEGF) when compared to controls. These findings demonstrate that sildenafil acts as a potent stimulator of angiogenesis and bone regeneration in atrophic non-unions