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Integrin alpha2beta1 plays a critical role in osteoblast response to micron-scale surface structure and surface energy of titanium substrates.

ABSTRACT: Efforts to improve bone response to biomaterials have focused on ligands that bind alpha5beta1 integrins. However, antibodies to alpha5beta1 reduce osteoblast proliferation but do not affect differentiation when cells are grown on titanium (Ti). beta1-silencing blocks the differentiation stimulus of Ti microtopography, suggesting that other beta1 partners are important. Stably alpha2-silenced MG63 human osteoblast-like cells were used to test whether alpha2beta1 specifically mediates osteoblast response to Ti surface micron-scale structure and energy. WT and alpha2-silenced MG63 cells were cultured on tissue culture polystyrene (TCPS) and Ti disks with different surface microtopographies: machined pretreatment (PT) surfaces [mean peak to valley roughness (R(a)) < 0.02 microm], PT surfaces that were grit-blasted and acid-etched (SLA; R(a) = 4 microm), and SLA with high surface energy (modSLA). Alkaline phosphatase (ALP), alpha2 and beta1 mRNA, but not alpha5, alpha v, beta3, type-I collagen, or osteocalcin, increased on SLA and modSLA at 6 days. Alpha2 increased at 8 days on TCPS and PT, but remained unchanged on SLA and modSLA. Alpha2-protein was reduced 70% in alpha2-siRNA cells, whereas alpha5-mRNA and protein were unaffected. Alpha2-knockdown blocked surface-dependent increases in beta1 and osteocalcin and decreases in cell number and increases in ALP and local factors typical of MG63 cells grown on SLA and modSLA [e.g., prostaglandin E(2), osteoprotegerin, latent and active TGF-beta1, and stimulatory effects of 1alpha,25(OH)(2)D(3) on these parameters]. This finding indicates that alpha2beta1 signaling is required for osteoblastic differentiation caused by Ti microstructure and surface energy, suggesting that conclusions based on cell behavior on TCPS are not predictive of behavior on other substrates or the mechanisms involved.

SUBMITTER: Olivares-Navarrete R

PROVIDER: S-EPMC2564982 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:A critical stage during osseointegration of a titanium (Ti) implant is primary bone remodeling, which involves cross talk among osteoclast precursors, osteoclasts, mesenchymal stem cells (MSCs), and osteoblasts. This phase couples the processes of bone formation and resorption. During remodeling, osteoclasts produce factors capable of regulating MSC migration and osteogenesis. Furthermore, they degrade primary bone, creating a foundation with a specific chemistry, stiffness, and morphology for osteoblasts to synthesize and calcify their matrix. MSCs and osteoblasts receiving cues from the implant surface produce factors capable of regulating osteoclasts in order to promote net new bone formation. The purpose of this study was to determine the effects Ti implant surfaces have on bone remodeling. Human MSCs and normal human osteoblasts (NHOsts) were cultured separately on 15 mm grade 2 smooth PT, hydrophobic-microrough SLA, hydrophilic-microrough Ti (mSLA) (Institut Straumann AG, Basel, Switzerland), or tissue culture polystyrene (TCPS). After 7d, conditioned media from surface cultures were used to treat human osteoclasts for 2d. Activity was measured by fluorescence of released collagen followed by mRNA quantification. This study demonstrates that MSC and NHOst cultures are able to suppress osteoclast activity in a surface dependent manner and osteoclast mRNA levels are selectively regulated by surface treatments. The substrate-dependent regulatory effect was mitigated when MSCs were silenced for integrin subunits and when conditioned media were denatured. These results indicate that MSCs and NHOsts regulate at least two aspects of remodeling: reduced fusion of new osteoclasts and reduced activity of existing osteoclasts. STATEMENT OF SIGNIFICANCE:In this study, we developed a novel in vitro model to study how microstructured and hydrophilic titanium implants impact bone remodeling for dental and orthopaedic applications. Our approach intersects biomaterials and systems physiology, revealing for the first time that implant surface properties are capable of regulating the communication among the cells involved in remodeling of primary bone during osseointegration. We believe that the basic research presented in our manuscript will provide important knowledge in our understanding of factors that impact implant success. Furthermore, it provides a solid foundation for the development of materials that enable rapid osseointegration and earlier loading times for implants in bone that has been compromised by trauma or disease.

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Integrin alpha2beta1 plays a critical role in osteoblast response to micron-scale surface structure and surface energy of titanium substrates.

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