VEGF-A, -C, -D, VEGFR1, -2, -3, PDGF-BB and FGF-2 join forces to induce vascular and lymphatic angiogenesis during bone healing of hip implants

Introduction

Angiogenic growth factors are a critical part of bone repair and regeneration in the aftermath of bone trauma. In the current study we monitored the spatiotemporal responses of angiogenic factors and receptors during the process of osseointegration of hip implants.

Materials and methods

Twenty-four patients having undergone primary total hip arthroplasty (THA) due to one-sided osteoarthritis (OA) were monitored during a period of 18 years (Y) by repeated measurements of plasma biomarkers as well as clinical and radiographic variables, the latter two showing all implants of the study to be well anchored throughout the follow-up. Eighty-one healthy donors divided into three gender- and age-matched subgroups and twenty OA patients awaiting THA, served as controls. Plasma was analyzed for vascular endothelial growth factor (VEGF)-A, VEGF-C, VEGF-D, vascular endothelial growth factor receptor 1 (VEGFR1) or sFlt-1, VEGFR2 (KDR/sFlk-1), VEGFR3 (sFlt-4), platelet derived growth factor–BB (PDGF-BB), fibroblast growth factor-2 (FGF-2) and placental growth factor (PIGF). Analysis of biomarkers was done by means of a high-sensitivity and wide dynamic range electrochemiluminescence technique allowing for detection of low levels and minor changes in biomarker levels. Spatiotemporal changes of biomarkers in THA patients during the follow-up were presented in the context of the four phases of endochondral bone repair.

Results

VEGF-A, VEGFR1, PDGF-BB and FGF-2 were significantly higher, whereas VEGF-C was significantly lower in presurgery OA patients versus healthy subjects but were all normalized shortly after implant surgery. VEGF-A, VEGF-C, VEGF-D, VEGFR2, VEGFR3, FGF-2 and PDGF-BB increased sharply 1–2 Y post-implant and reached a peak significantly above healthy control subjects at 5–7 Y after implant insertion before returning to control level 13-15Y post-surgery, except for VEGF-D that returned to control level at 7Y post-implant. VEGFR1 decreased to the level of healthy subjects at 6 W post-THA and remained there throughout the study. PIGF did not differ from healthy subjects at any point during the follow-up.

Conclusion

Increased levels of VEGF-A, VEGFR1, PDGF-BB and FGF-2 and reduced VEGF-C in presurgery OA relative healthy subjects support a cartilage protective or disease-inducing role in osteoarthritis. The concerted increase by all proangiogenic factors of the study, except VEGFR1 and PIGF, at 5 Y post-implant lend strong support to this being the phase of bone repair when blood and lymph vessels invade the avascular calcified hypertrophic cartilage and trigger its remodeling into bone in hip arthroplasty patients.