Cigarette smoke inhalation impairs angiogenesis in early bone healing processes and delays fracture union

Abstract

Aims Cigarette smoking has a negative impact on the skeletal system, causes a decrease in bone mass in both young and old patients, and is considered a risk factor for the development of osteoporosis. In addition, it disturbs the bone healing process and prolongs the healing time after fractures. The mechanisms by which cigarette smoking impairs fracture healing are not fully understood. There are few studies reporting the effects of cigarette smoking on new blood vessel formation during the early stage of fracture healing. We tested the hypothesis that cigarette smoke inhalation may suppress angiogenesis and delay fracture healing. Methods We established a custom-made chamber with airflow for rats to inhale cigarette smoke continuously, and tested our hypothesis using a femoral osteotomy model, radiograph and microCT imaging, and various biomechanical and biological tests. Results In the smoking group, Western blot analysis and immunohistochemical staining revealed less expression of vascular endothelial growth factor (VEGF) and von Willebrand factor (vWF). The smoking group also had a lower microvessel density than the control group. Image and biochemical analysis also demonstrated delayed bone healing. Conclusion Cigarette smoke inhalation was associated with decreased expression of angiogenic markers in the early bone healing phase and with impaired bone healing. Cite this article: Bone Joint Res. 2020;9(3):99–107.

Risk Factors for New Vertebral Fracture After Percutaneous Vertebroplasty for Osteoporotic Vertebral Compression Fractures

“… 14 In particular, nicotine affects the bones’ blood supply and ability to heal. 15 Costa-Rodrigues et al 16 showed that nicotine in smokers’ plasma could act directly on osteoclasts and induce differentiation and worsening of osteoporosis. Joehanes et al 17 conducted genetic tests on 15,907 blood samples and showed that harmful substances in tobacco could cause DNA methylation; this affects the regeneration and transformation of bone tissue, causing or aggravating osteoporosis.…”

Skeletal System Biology and Smoke Damage: From Basic Science to Medical Clinic

“…Several studies have shown that there is a close and direct association between cigarette smoking, decreased BMD, and impaired fracture healing, even though the underlying mechanisms have not yet been fully understood. For example, it has been reported that smoke inhalation causes a decrease in the expression of angiogenic markers and compromises bone healing, as well as possibly leading to a delay in fracture union [ 58 ]. However, many substances contained in cigarettes have a negative effect on bone healing and it is not clear whether a single toxic substance or several toxic compounds may be responsible for these effects on bone tissue.…”

“…According to some evidence, cigarette smoke can impair every step in the fracture healing process ( Figure 1 ). In this regard, Chang et al conducted a study to evaluate the effects of cigarette smoke on the formation of new blood vessels during the early stage of fracture healing [ 58 ]. The authors observed that cigarette smoke inhalation results in decreased expression of angiogenic markers, such as vascular endothelial growth factor (VEGF) and von Willebrand factor (vWF), during the early phase of bone healing, with a consequent decrease in the density of newly formed microvessels.…”

“…The authors observed that cigarette smoke inhalation results in decreased expression of angiogenic markers, such as vascular endothelial growth factor (VEGF) and von Willebrand factor (vWF), during the early phase of bone healing, with a consequent decrease in the density of newly formed microvessels. Their findings suggest that smoking may impair healing by altering fracture hematoma formation [ 58 ].…”

Systemically impaired fracture healing in small animal research: A review of fracture repair models

“…In addition, there is considerable evidence of the negative effects of smoking on bone healing and union rates 5,99 . Smoking impairs healing via several mechanisms, including a reduction in blood supply to the injury site, increased levels of reactive oxygen species, reduced levels of circulating antioxidants, and nicotine toxicity in osteoblasts 100 . Moreover, multiple in vivo animal studies have shown that exposure to high levels of nicotine and tobacco extract inhibits bony healing and results in reduced mechanical strength 101‐103 .…”