Effect of titanium ions on the Hippo/YAP signaling pathway in regulating biological behaviors of MC3T3‐E1 osteoblasts

Abstract

Titanium (Ti) and its corresponding alloys have been widely applied in dental and orthopedic implants. Owing to abrasion and corrosion of implants in the unfavorable electrolytic aqueous environment of the host body, Ti ions could be released from implants and accumulated in local tissues. Recent studies have found that excessive Ti ions were toxic to osteoblasts in adjacent bone tissues and subsequently influenced long-term effects on implant prostheses. However, the potential molecular mechanisms underlying the damage to osteoblasts induced by Ti ions remained unclear. Hippo signaling has been confirmed to be involved in organ size and tissue regeneration in many organs, while its roles in osteoblasts differentiation and bone repair remained elusive. Therefore, we hypothesize that YAP, a regulator of Hippo pathway, inhibited osteoblast growth, skeletal development and bone repair, as well as excessive Ti ions promoted the progression of YAP activation. This study aimed to explore the role of Hippo/YAP signaling pathway in the biotoxicity effect of Ti ions on osteoblast behaviors. Here, we confirmed that 10 ppm Ti ions, a minimum concentration gradient previously reported that was capable of suppressing osteoblasts growth, induced nuclear expression of YAP in osteoblasts in our study. Furthermore, 10 ppm Ti ion-induced YAP activation was found to downregulate osteogenic differentiation of MC3T3-E1 cells. Most importantly, the hypothesis we proposed that knockdown of YAP did reverse the inhibitory effect of 10 ppm Ti ions on osteogenesis has been verified. Taken together, our work provides insights into the mechanism of which YAP is involved in regulating osteoblast behaviors under the effect of Ti ions, which may help to develop therapeutic applications for Ti implant failures and peri-implantitis.

Role of MAPK/JNK signaling pathway on the regulation of biological behaviors of MC3T3‑E1 osteoblasts under titanium ion exposure

“…a previous study has demonstrated that 10 ppm Ti ions was a toxic concentration for osteoblast proliferation (20). in the present study, the effects of 10 ppm Ti ions on osteoblast adhesion and early differentiation characteristics were investigated further.…”

“…at present, studies reporting the effects of titanium corrosion products on osteoblasts are insufficient. A previous study reported that 10 ppm Ti ions, which is the minimum toxic concentration, was capable of suppressing the growth whilst promoting the nuclear translocation of Yes-associated protein in osteoblast-like Mc3T3-e1 cells (20). although the negative effect of Ti ion exposure has been explored in preliminary studies, the underlying regulatory mechanism of the effects mediated by excessive Ti ion accumulation during osteoblast differentiation remain poorly understood.…”

Osseointegration of titanium dental implant under fluoride exposure in rabbits: Micro‐CT and histomorphometry study

“…The destructive oxide layer could, in turn, alter the biointerface characteristics of titanium, which is essential for cell adhesion and growth (Santiago‐Medina, Sundaram, & Diffoot‐Carlo, ). Moreover, released titanium ions, the degradation products of corrosion, are toxic to osteoblast viability and differentiation (Zhu et al, ). However, it is rarely reported on titanium implant osseointegration under fluoride exposure.…”

Are Titania Photocatalysts and Titanium Implants Safe? Review on the Toxicity of Titanium Compounds

“…The cellular response to titanium particles/ions has been investigated mainly for oral mucosa cells. For example, it has been found that the exposure of mouse osteoblast-like MC3T3-E1 cells to Ti ions inhibits cell proliferation (in dependence on the concentration and time), and induces nuclear expression of Yes-associated protein YAP (a key transcription co-activator, the activity of which is inhibited by the Hippo signaling pathway) in osteoblasts, resulting in down regulation of osteogenic differentiation of MC3T3-E1 cells [ 77 ]. According to the in vivo study on detection of lactate dehydrogenase (LDH), interleukin (IL) and activated nuclear factor-kappa B (NF-κB), inflammatory reaction (high content of IL-6) and activated NF-κB have been detected around a titanium implant [ 78 ].…”