Expression of VEGF, BMP-2, and the OPG/RANK axis as indicators of osseointegration: a comparative clinical and experimental study of titanium implants with functional protective coatings

O.O. Bondarenko; A.E. Lievykh; N.S. Bondarenko; A.G. Bozhko; O.Ye. Loskutov; I.S.  Shponka

doi:10.26641/2307-0404.2025.4.348747

Authors

O.O. Bondarenko Dnipro State Medical University, Volodymyra Vernadskoho str., 9, Dnipro, 49044, Ukraine https://orcid.org/0000-0002-9739-9219
A.E. Lievykh Dnipro State Medical University, Volodymyra Vernadskoho str., 9, Dnipro, 49044, Ukraine https://orcid.org/0000-0002-0615-5092
N.S. Bondarenko Dnipro State Medical University, Volodymyra Vernadskoho str., 9, Dnipro, 49044, Ukraine
A.G. Bozhko Dnipro State Medical University, Volodymyra Vernadskoho str., 9, Dnipro, 49044, Ukraine https://orcid.org/0000-0002-1054-7574
O.Ye. Loskutov Dnipro State Medical University, Volodymyra Vernadskoho str., 9, Dnipro, 49044, Ukraine https://orcid.org/0000-0003-0579-5642
I.S. Shponka Dnipro State Medical University, Volodymyra Vernadskoho str., 9, Dnipro, 49044, Ukraine https://orcid.org/0000-0002-7561-6489

DOI:

https://doi.org/10.26641/2307-0404.2025.4.348747

Keywords:

osteoinduction, osteoconduction, osseointegration, titanium implant, alumina, translational study, vascular-endothelial growth factor (VEGF), receptor of vascular-endothelial growth factor (VEGFR), bone morphogenetic protein 2 (BMP-2), osteoprotegerin/receptor activator of nuclear factor κB (OPG/RANK) axis, bone remodeling, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA)

Abstract

The objective of the present study was to validate key molecular markers of bone tissue repair as indicators of osseointegration on systemic and local levels, and evaluate their translational parallelism. This was achieved by comparing the configurational consistency of expression profiles between an experimental rat model and a pilot clinical investigation in human patients to synchronize systemic and local molecular responses. The hypothesis was that alumina-coated titanium implants would exhibit faster dynamics of angiogenic and osteogenic biomarkers, indicating accelerated osteoinduction, osteoconduction, and osseointegration compared with uncoated titanium. The pilot clinical study comprised the patients after total hip arthroplasty (n=6): three with uncoated titanium implants and three with alumina ceramics. Serum samples were collected from these patients in one and six months post-surgery. The experimental rat model comprised 160 Wistar females implanted with modified intrafemoral implants (seven surface types, including uncoated and alumina-coated titanium), with serum and peri-implant tissue samples collected in one, two, four, and eight weeks. Serum levels of vascular endothelial growth factor, bone morphogenetic protein 2, and osteoprotegerin were determined by enzyme-linked immunosorbent assay, while the corresponding local expression of vascular endothelial growth factor receptor, bone morphogenetic protein 2, and receptor activator of nuclear factor kappa-B was assessed by immunohistochemistry. The results demonstrated that alumina-coated implants induced an accelerated and synchronized molecular cascade in the rat model, which was qualitatively replicated in the clinical cohort. The systemic vascular endothelial growth factor peak manifested early, at one week in rats and one month in humans, and exhibited a strong parallelism with local microvessel density in the animal model, confirming rapid angiogenic activation. In both species, the expression of bone morphogenetic protein 2 increased earlier and to a greater extent in the alumina-coated groups, indicating more rapid osteoinduction. Local receptor activator of nuclear factor kappa-B activity demonstrated an early rise and a four-week peak in the groups with coated implants, consistent with controlled and timely bone remodelling. The study indicates that alumina coatings promote accelerated osseointegration by advancing the time course of healing, a conclusion supported by the observed translational parallelism of the investigated markers.

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