Dandan Pei

The diabetic microenvironment intensifies M1-type macrophage–mediated inflammation and impairs bone regeneration. Glycophagy—a process of glycogen-selective autophagy that degrades intracellular glycogen into glucose—is essential for maintaining glucose homeostasis under metabolic stress. The role of glycophagy in regulating M1-type polarization remains unclear. In this study, we found that M1-type polarization correlated with increased glycophagy in a diabetic mandibular bone defect model. Proteomic analysis revealed the involvement of the glycophagy mediator acid α-glucosidase (GAA) in M1-type polarization in diabetic bone callus. Mechanistically, the upregulation of GAA drove M1-type polarization to inhibit osteogenesis under high-glucose conditions by activating the mTORC1 signaling pathway. Transplant of GAA-silenced macrophages restored the osteogenic capability in mandibular injury in diabetic rats. In conclusion, our study unravels the regulation of a fundamental mechanism of M1-type polarization by the glycophagy mediator GAA, providing insights relevant for promoting bone generation in diabetic individuals.

The advent of 3D-printing technology, which is capable of on-demand fabrication, has ushered in a new era for fixed implant prosthodontics. Over the past decade, immediately loaded 3D-printed titanium implants have demonstrated predictable clinical outcomes in human jaws, highlighting their superior osseointegration strength, which is attributed to their increased surface roughness. However, the biomechanical mechanisms underlying this enhanced osseointegration strength remain elusive, thereby impeding the standardization and broader clinical application of 3D-printed titanium implants. Experimental 3D-printed titanium implants were fabricated via selective laser melting (SLM), and conventional sandblasted and acid-etched titanium implants (CNC-SLA) served as the control group. Implant surfaces were characterized with scanning electron microscopy, surface profilometry, energy-dispersive X-ray spectroscopy, and a contact angle meter. Implants (n = 10) were surgically inserted into the femoral condyle of New Zealand rabbits. At weeks 1, 2, and 8, micro-CT and undecalcified histological sections were used to assess histological osseointegration (n = 6), whereas removal torque analysis was performed to evaluate osseointegration strength (n = 4). At week 8, microscale finite element analysis of different bone-implant interfaces was conducted to predict the peri-implant bone strain under multidirectional implant loading. The surface roughness of the SLM implants was significantly greater than that of the CNC-SLA implants. Histological osseointegration assessments revealed equal levels of SLM and CNC-SLA implants at weeks 1, 2, and 8. Notably, after week 2, bone interlocking phenomenon appeared on the SLM implants. The removal torque for the SLM implants at week 2 were significantly greater (P < 0.05) than that for the CNC-SLA implants at the same time point and was comparable to the CNC-SLA implants at week 8 (P = 0.775). The removal torque for the SLM implants at week 8 was further increased. Microscale finite element analysis revealed that the rough surface of the SLM implants dispersed harmful strains at the bone-implant interface into the surrounding bone, thereby mitigating the risk of damage to the bone-implant interface. The rough surface of 3D-printed titanium implants fosters microscale bone interlocking and alleviates peri-implant bone strain concentration, which is a promising biomechanical basis for osseointegration strength.

Autophagy plays an important role in determining stem‐cell differentiation. During the osteogenic differentiation of mesenchymal stem cells (MSCs), autophagosome formation is upregulated but the reason is unknown. A long‐standing quest in the autophagy field is to find the membrane origin of autophagosomes. In this study, cytoplasmic coat protein complex II (COPII) vesicles, endoplasmic reticulum‐derived vesicles responsible for the transport of storage proteins to the Golgi, are demonstrated to be a critical source of osteoblastic autophagosomal membrane. A significant correlation between the number of COPII vesicle and the autophagy level is identified in the rat bone tissues. Disruption of COPII vesicles restrained osteogenesis and decreased the number and size of autophagosomes. SEC31a (an outer coat protein of COPII vesicle) is found to be vital to regulate COPII vesicle‐dependent autophagosome formation via interacting with ATG9a of autophagosomal seed vesicles. The interference of Sec31a inhibited autophagosome formation and osteogenesis in vitro and in vivo. These results identified a novel mechanism of autophagosome formation in osteogenic differentiation of stem cells and identified SEC31a as a critical protein that mediates the interplay between COPII and ATG9a vesicles. These findings broaden the understanding of the regulatory mechanism in the osteogenic differentiation of MSCs.

Editorial on the Research Topic Advanced biomaterials for hard tissue repair and regeneration Bone and tooth are typical hard tissues in vertebrates. Due to hierarchical structural characteristics and excellent mechanical properties, hard tissues play important roles for human body, such as health protection, movement support, and food mastication. Once hard tissue defect occurs, our living quality will be seriously affected. In general, hard tissues lack the ability of self-repair, except for the regeneration ability of bone for small-scale defects. As a result, the past few decades have witnessed great progress in the field of biomaterials for hard tissue repair. Actually, both bone and tooth are masterpieces of biomineralization in nature, the repair and regeneration of hard tissues should be performed in a biomimetic way. Therefore, this Research Topic provides a comprehensive overview of the current state of the art regarding advanced biomaterials used to repair or regenerate damaged hard tissues, as well as to highlight the most promising advanced strategies other than suggest the future direction in the field. In the present Research Topic, 154 authors from all over the world decided to publish their outstanding and promising results.

A growing number of studies indicate that mitochondrial dysfunction serves as a pathological mechanism for periodontitis. Therefore, this two-sample Mendelian randomization (MR) study was carried out to explore the causal associations between mitochondrial biological function and periodontitis, because the specific nature of this causal relationship remains inconclusive in existing MR studies. Inverse variance weighting, Mendelian randomization-Egger, weighted mode, simple mode, and weighted median analyses were performed to assess the causal relationships between the exposure factors and periodontitis. The results of the present study revealed a causal association between periodontitis and medium-chain specific acyl-CoA dehydrogenase (MCAD), malonyl-CoA decarboxylase (MLYCD), glutaredoxin 2 (Grx2), oligoribonuclease (ORN), and pyruvate carboxylase (PC). Notably, MCAD and MLYCD are causally linked to periodontitis, and serve as protective factors. However, Grx2, ORN, and PC function as risk factors for periodontitis. Our study established a causal relationship between mitochondrial biological function and periodontitis, and such insights may provide a promising approach for treating periodontitis via mitochondrial regulation.

Bone mineralization is a sophisticated regulated process composed of crystalline calcium phosphate and collagen fibril. Autophagy, an evolutionarily conserved degradation system, whereby double-membrane vesicles deliver intracellular macromolecules and organelles to lysosomes for degradation, has recently been shown to play an essential role in mineralization. However, the formation of autophagosomes in mineralization remains to be determined. Here, we show that Coat Protein Complex I (COPI), responsible for Golgi-to-ER transport, plays a pivotal role in autophagosome formation in mineralization. COPI vesicles were increased after osteoinduction, and COPI vesicle disruption impaired osteogenesis. Mechanistically, COPI regulates autophagy activity via the mTOR complex 1 (mTORC1) pathway, a key regulator of autophagy. Inhibition of mTOR1 rescues the impaired osteogenesis by activating autophagy. Collectively, our study highlights the functional importance of COPI in mineralization and identifies COPI as a potential therapeutic target for treating bone-related diseases.

Three-dimensional printing is a revolutionary strategy to fabricate dental implants. Especially, 3D-printed dental implants modified with nanoscaled titanium oxide layer (H-SLM) have impressively shown quick osseointegration, but the accurate mechanism remains elusive. Herein, we unmask a domino effect that the hydrophilic surface of the H-SLM facilitates blood wetting, enhances the blood shear rate, promotes blood clotting, and changes clot features for quick osseointegration. Combining computational fluid dynamic simulation and biological verification, we find a blood shear rate during blood wetting of the hydrophilic H-SLM 1.2-fold higher than that of the raw 3D-printed implant, which activates blood clot formation. Blood clots formed on the hydrophilic H-SLM demonstrate anti-inflammatory and pro-osteogenesis effects, leading to a 1.5-fold higher bone-to-implant contact and a 1.8-fold higher mechanical anchorage at the early stage of osseointegration. This mechanism deepens current knowledge between osseointegration speed and implant surface characteristics, which is instructive in surface nanoscaled modification of multiple 3D-printed intrabony implants.