With millions of new dental and orthopedic implants inserted annually, periprosthetic osteolysis becomes a major concern. In dentistry, peri-implantitis management includes cleaning using ultrasonic scaling. We examined whether ultrasonic scaling releases titanium particles and induces inflammation and osteolysis. Titanium discs with machined, sandblasted/acid-etched and sandblasted surfaces were subjected to ultrasonic scaling and we physically and chemically characterized the released particles. These particles induced a severe inflammatory response in macrophages and stimulated osteoclastogenesis. The number of released particles and their chemical composition and nanotopography had a significant effect on the inflammatory response. Sandblasted surfaces released the highest number of particles with the greatest nanoroughness properties. Particles from sandblasted/acid-etched discs induced a milder inflammatory response than those from sandblasted discs but a stronger inflammatory response than those from machined discs. Titanium particles were then embedded in fibrin membranes placed on mouse calvariae for 5 weeks. Using micro-CT, we observed that particles from sandblasted discs induced more osteolysis than those from sandblasted/acid-etched discs. In summary, ultrasonic scaling of titanium implants releases particles in a surface type-dependent manner and may aggravate peri-implantitis. Future studies should assess whether surface roughening affects the extent of released wear particles and aseptic loosening of orthopedic implants.

The worldwide number of dental implants and orthopedic prostheses is steadily increasing. Orthopedic implant loosening, in the absence of infection, is mostly attributable to the generation of wear debris. Dental peri-implantitis is characterized by a multifactorial etiology and is the main cause of implant failure. It consists of a peri-implant inflammatory lesion that often results in loss of supporting bone. Disease management includes cleaning the surrounding flora by hand instruments, ultrasonic tips, lasers, or chemical agents. We recently published a paper indicating that US scaling of titanium (Ti) implants releases particles that provoke an inflammatory response and osteolysis. Here we show that a strong inflammatory response occurs; however, very few of the titanium particles are phagocytosed by the macrophages. We then measured a dramatic Ti particle-induced stimulation of IL1β, IL6, and TNFα secretion by these macrophages using multiplex immunoassay. The particle-induced expression profile, examined by FACS, also indicated an M1 macrophage polarization. To assess how the secreted cytokines contributed to the paracrine exacerbation of the inflammatory response and to osteoclastogenesis, we treated macrophage/preosteoclast cultures with neutralizing antibodies against IL1β, IL6, or TNFα. We found that anti-TNFα antibodies attenuated the overall expression of both the inflammatory cytokines and osteoclastogenesis. On the other hand, anti-IL1β antibodies affected osteoclastogenesis but not the paracrine expression of inflammatory cytokines, whereas anti-IL6 antibodies did the opposite. We then tested these neutralizing antibodies in vivo using our mouse calvarial model of Ti particle-induced osteolysis and microCT analysis. Here, all neutralizing antibodies, administered by intraperitoneal injection, completely abrogated the particle-induced osteolysis. This suggests that blockage of paracrine inflammatory stimulation and osteoclastogenesis are similarly effective in preventing bone resorption induced by Ti particles. Blocking both the inflammation and osteoclastogenesis by anti-TNFα antibodies, incorporated locally into a slow-release membrane, also significantly prevented osteolysis. The osteolytic inflammatory response, fueled by ultrasonic scaling of Ti implants, results from an inflammatory positive feedback loop and osteoclastogenic stimulation. Our findings suggest that blocking IL1β, IL6, and/or TNFα systemically or locally around titanium implants is a promising therapeutic approach for the clinical management of peri-implant bone loss.

A major flaw in autism spectrum disorder (ASD) management is late diagnosis. Activity-dependent neuroprotective protein (ADNP) is a most frequent de novo mutated ASD-related gene. Functionally, ADNP protects nerve cells against electrical blockade. In mice, complete Adnp deficiency results in dysregulation of over 400 genes and failure to form a brain. Adnp haploinsufficiency results in cognitive and social deficiencies coupled to sex- and age-dependent deficits in the key microtubule and ion channel pathways. Here, collaborating with parents/caregivers globally, we discovered premature tooth eruption as a potential early diagnostic biomarker for ADNP mutation. The parents of 44/54 ADNP-mutated children reported an almost full erupted dentition by 1 year of age, including molars and only 10 of the children had teeth within the normal developmental time range. Looking at Adnp-deficient mice, by computed tomography, showed significantly smaller dental sacs and tooth buds at 5 days of age in the deficient mice compared to littermate controls. There was only trending at 2 days, implicating age-dependent dysregulation of teething in Adnp-deficient mice. Allen Atlas analysis showed Adnp expression in the jaw area. RNA sequencing (RNAseq) and gene array analysis of human ADNP-mutated lymphoblastoids, whole-mouse embryos and mouse brains identified dysregulation of bone/nervous system-controlling genes resulting from ADNP mutation/deficiency (for example, BMP1 and BMP4). AKAP6, discovered here as a major gene regulated by ADNP, also links cognition and bone maintenance. To the best of our knowledge, this is the first time that early primary (deciduous) teething is related to the ADNP syndrome, providing for early/simple diagnosis and paving the path to early intervention/specialized treatment plan.

Correction to: Translational Psychiatry (2017) 7, e1043; doi:10.1038/tp.2017.27; published online 21 February 2017 Several entries in Table 1 use protein change annotations that do not comply with Human Genome Variation Society nomenclature. The nomenclature corrections (obtained from https://mutalyzer.

The common use of dental and orthopedic implants calls for special attention to the immune response leading to peri-prosthetic bone loss and implant failure. In addition to the well-established microbial etiology for oral implant failure, wear debris and in particular titanium (Ti) particles (TiP) in the implant vicinity are an important trigger of inflammation and activation of bone resorption around oral and orthopedic implants, presenting an unmet medical need. Here, we employed bacterial-derived lipopolysaccharides (LPS) to model infection and TiP to model aseptic inflammation and osteolysis. We assessed inflammation in vitro by measuring IL1β, IL6 and TNFα mRNA expression in primary macrophages, osteoclastogenesis in RANKL-induced bone marrow derived pre-osteoclasts and osteolysis in vivo in a mouse calvarial model. We also assessed the trans-epithelial penetrability and safety of the tested compound in rats. Our results show that a lipophilic super-active derivative of vasoactive intestinal peptide (VIP), namely stearyl-norleucine-VIP (SNV) presented superior anti-inflammatory and anti-osteoclastogenic effects compared to VIP in vitro. In the bacterial infection model (LPS), SNV significantly reduced IL1β expression, while VIP increased IL6 expression. In the aseptic models of osteolysis, SNV showed greater suppression of in vitro osteoclastogenesis than VIP, and significantly inhibited inflammation-induced osteolysis in vivo. We also observed that expression levels of the VIP receptor VPAC-2, but not that of VPAC-1, dramatically decreased during osteoclast differentiation. Importantly, SNV previously shown to have an increased stability compared to VIP, showed here significant trans-epithelial penetration and a clean toxicological profile, presenting a novel drug candidate that could be applied topically to counter both aseptic and infection-related bone destruction.