Locking plate fixation versus intramedullary nail fixation for the treatment of multifragmentary proximal humerus fractures (OTA/AO type 11C): a preliminary comparison of clinical efficacy.

BACKGROUND: This study aimed to compare the clinical efficacy of locking plate and intramedullary nail fixations in the treatment of patients with OTA/AO type 11C proximal humerus fractures. METHODS: We retrospectively analyzed the data of patients with OTA/AO type 11C1.1 and 11C3.1 proximal humerus fractures who underwent surgery at our institution from June 2012 to June 2017. Perioperative indicators, postoperative morphological parameters of the proximal humerus, and Constant-Murley scores were evaluated and compared. RESULTS: Sixty-eight patients with OTA/AO type 11C1.1 and 11C3.1 proximal humerus fractures were enrolled in this study. Overall, 35 patients underwent open reduction and plate screw internal fixation, and 33 patients underwent limited open reduction and locking of the proximal humerus with intramedullary nail internal fixation. The total cohort had a mean follow-up duration of 17.8 months. The mean operation time of the locking plate group was significantly longer than that of the intramedullary nail group (P < 0.05), while the mean bleeding volume was significantly higher in the locking plate group than that in the intramedullary nail group (P < 0.05). The initial neck-shaft angles, final neck-shaft angles, forward flexion ranges, or Constant-Murley scores did not show significant differences between the two groups (P > 0.05). Complications, including screw penetrations, acromion impingement syndrome, infection, and aseptic necrosis of the humeral head, occurred in 8 patients (8/35, 22.8%) in the locking plate group and 5 patients in the intramedullary nail group (5/33, 15.1%; including malunion and acromion impingement syndrome), with no significant difference between the groups (P > 0.05). CONCLUSIONS: Similar satisfactory functional results can be achieved with locking plates and intramedullary nailing for OTA/AO type 11C1.1 and 11C3.1 proximal humerus fractures, with no significant difference in the number of complications between these two techniques. However, intramedullary nailing has advantages over locking plates for OTA/AO type 11C1.1 and 11C3.1 proximal humerus fractures in terms of operation time and bleeding volume.

Protective Role of ß-Sitosterol in Glucocorticoid-Induced Osteoporosis in Rats Via the RANKL/OPG Pathway.

Introduction: Osteoporosis affects approximately 10% of the population worldwide. ß-sitosterol (BSS), a major phytosterol in plants, has been claimed for centuries to have numerous medical benefits, including bone strengthening. This study aimed to find the benefit of BSS in treating osteoporosis according to traditional methods and to investigate the protective effect of BSS on glucocorticoid-induced osteoporosis in rats. Design: Wistar rats were randomly assigned to one of four groups: the control group, the dexamethasone (DEX) group and one of two BSS-treated osteoporosis groups (100 and 200 mg/kg). Blood samples and femur bones were collected for histopathology, immunohistochemistry, biochemical and mRNA expression analysis. Results: The results indicated that BSS (100 and 200 mg/kg) increased bone length, bone weight and bone mineral density (BMD) and suppressed DEX-induced reduction in body weight, dose-dependently. Mechanistically, BSS (100 and 200 mg/kg) treatment alleviated the increase of bone resorption markers and the decline of osteogenic markers, which might be partially mediated by regulation of nuclear factor kappa-ß ligand/osteoprotegerin (RANKL/OPG) and RunX2 pathways. The immunohistochemical inducible nitric oxide synthase (iNOS) results of the rats' distal femur were negative in all groups. However, except in the DEX group, the endothelial nitric oxide synthase (eNOS) color reaction in osteoblasts was strongly positive in the other 3 groups. These results suggest that BSS showed promising effects in protection against glucocorticoid-induced osteoporosis by protecting osteoblasts and suppressing osteoclastogenesis.

Antiosteoporosis effect of geraniin on ovariectomy-induced osteoporosis in experimental rats.

Osteoporosis is a skeletal condition that is characterized by decreasing bone density and deteriorating bone mass. The plant-based phytoconstituent such as geraniin possesses better therapeutic potentials in biomedical field. In the current experimental study, we planned to scrutinize the therapeutic potential of geraniin against ovariectomy (OVX)-induced osteoporosis in rats and find the possible mechanism. Healthy Sprague Dawley rats were randomized into six groups and subjected to geraniin and alendronate (ALN) treatment for 10 weeks. Body weight, uterus, femur weight, bone biochemical, bone turnover markers, inflammatory cytokine, calcium, phosphorus, vitamin D (Vit D), urine, hormones, and antioxidant level were estimated. Geraniin significantly (p < .001) reduced the level of bone turnover markers including beta-CrossLaps (ß-CTx), ALN, osteocalcin (OC), alkaline phosphatase (ALP), and bone Gla protein (BGP); reduced the biomechanical parameters including maximum load, energy, stiffness, maximum stress, and Young's modulus; reduced the level of calcium (Ca) and phosphorus (P); and increased the level of vitamin D (Vit D) as compared with OVX-induced osteoporosis rats. Geraniin increased the level of bone structure parameters, namely bone mineral density, bone mineral content, tissue mineral density, bone volume fraction, and trabecular number; increased the level of osteoprotegerin (OPG) and OPG/RANKL; and reduced the level of receptor activator of nuclear factor kappa-Β ligand (RANKL). Geraniin significantly (p < .001) increased the level of glutathione (GSH) and reduced the level of malonaldehyde (MDA) in the liver, intestine, and bone of OVX-induced osteoporosis rats. Geraniin significantly (p < .001) decreased the level of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) pro-inflammatory cytokines. We also argue that geraniin could be an excellent candidate to treat and control bone-related disease or disorders.

Second near-infrared photothermal-amplified immunotherapy using photoactivatable composite nanostimulators.

BACKGROUND: The construction of a nanoimmune controlled-release system that spatiotemporally recognizes tumor lesions and stimulates the immune system response step by step is one of the most potent cancer treatment strategies for improving the sensitivity of immunotherapy response. RESULTS: Here, a composite nanostimulator (CNS) was constructed for the release of second near-infrared (NIR-II) photothermal-mediated immune agents, thereby achieving spatiotemporally controllable photothermal-synergized immunotherapy. CNS nanoparticles comprise thermosensitive liposomes as an outer shell and are internally loaded with a NIR-II photothermal agent, copper sulfide (CuS), toll-like receptor-9 (TLR-9) agonist, cytosine-phospho-guanine oligodeoxynucleotides, and programmed death-ligand 1 (PD-L1) inhibitors (JQ1). Following NIR-II photoirradiation, CuS enabled the rapid elevation of localized temperature, achieving tumor ablation and induction of immunogenic cell death (ICD) as well as disruption of the lipid shell, enabling the precise release of two immune-therapeutical drugs in the tumor region. Combining ICD, TLR-9 stimulation, and inhibited expression of PD-L1 allows the subsequent enhancement of dendritic cell maturation and increases infiltration of cytotoxic T lymphocytes, facilitating regional antitumor immune responses. CONCLUSION: CNS nanoparticle-mediated photothermal-synergized immunotherapy efficiently suppressed the growth of primary and distant tumors in two mouse models and prevented pulmonary metastasis. This study thus provides a novel sight into photo-controllably safe and efficient immunotherapy.

How to get better TAD? Relationship between anteversion angle of nail and position of femoral neck guide pin during nailing of intertrochanteric fractures.

BACKGROUND: To demonstrate the correlation between guide pin-shaft angle (PSA) at the anteroposterior film and anteversion angle of guide pin at the lateral film and investigate whether excellent tip-apex distance (TAD) can be obtained by changing the entry point via axial rotation of the main intramedullary nail. METHODS: Fifty patients with intertrochanteric femoral fractures (IFFs) undergoing internal fixation with intramedullary nails under 2D fluoroscopy were retrospectively enrolled. Both of the PSA at the anteroposterior film and anteversion angle at the lateral film before and after adjustment of the guide pin were collected. Pearson correlation analysis was performed to investigate their correlation. Intraoperative and postoperative outcomes were recorded. Furthermore, the software of Mimics 10.0 and Pro/E were used to establish the 3D models of the proximal femur and main intramedullary nail/guide pin, respectively. Surgery was simulated on the Pro/E software platform and solid geometry analysis was conducted to calculate the correlation between the PSA and the anteversion angle. RESULTS: Pearson correlation analysis indicated there was a positive correlation between PSA and anteversion angle, with the correlation coefficient of 0.902 (p < 0.01). By altering the PSA and anteversion angle, TAD was adjusted to be less than 25 mm in all patients. The mean operative time, fluoroscopy time and length of hospital stay were 65.82 ± 11.16 min, 2.03 ± 0.79 min and 6.66 ± 2.49 d. Thirty-one patients received blood transfusions (3.55 ± 1.95 U). Fracture reduction was considered to be good or acceptable in all patients. Complications occurred only in 6 patients (12.00%). At a 3-month follow-up, the mean Timed Up and Go was 31.54 ± 20.95 s and Harris Hip Score was 72.88 ± 8.79. The 3D surgery model also showed when the main intramedullary nail was externally rotated or internally rotated of 20° at the standard location, the PSA of guide pin at the anteroposterior position and anteversion angle of the guide pin at the lateral position were simultaneously increased or decreased. CONCLUSION: Our findings suggest altering the PSA and anteversion angle may be beneficial for obtaining excellent TAD and achieving superior outcomes.

Computed Tomography Imaging-Based Preoperative Virtual Simulation for Calcaneal Fractures Reduction.

Reduction of calcaneal fractures via a small incision approach at the sinus tarsi is technically difficult. This study was undertaken to determine if preoperative virtual simulation based on computed tomographic data improves reduction and reduces complications. Fifty-five patients with calcaneal fractures were treated via the sinus tarsi approach with minimally invasive plates between February 2013 and December 2015. DICOM files obtained from computed tomographic imaging preoperatively were imported into Superimage software, and virtual surgery was performed. Preoperative planning time, operative time, and complications were recorded. Clinical function was analyzed with radiology and with the American Orthopaedic Foot and Ankle Society and visual analogue scale scores. As a result, preoperative planning time was 30.7 ± 4.1 minutes, which increased with the severity of the fracture (Sanders III vs Sanders II: 34.2 ± 2.5 minutes vs 27.8 ± 2.7 minutes), which was in line with the real surgery, with a mean operative time of 86.7 ± 4.5 minutes (Sanders III vs Sanders II: 89.5 ± 2.7 minutes vs 84.3 ± 4.4 minutes). Radiologic results indicated that the calcaneal width, length, height, Böhler angle, and Gissane angle were significantly corrected from preoperatively to postoperatively. After a mean follow-up of 21.5 ± 6.1 months, no complications were observed. The mean American Orthopaedic Foot and Ankle Society score was 88.7 ± 4.0, with an excellent/good rate of 94.5% (52 of 55). The mean visual analogue scale score was 0.8 ± 0.9. In conclusion, preoperative virtual simulation may be efficient to promote accomplishment of sinus tarsi surgery, and this step may help improve outcomes for calcaneal fractures.

Advances in magnesium-containing bioceramics for bone repair.

Reconstruction of bone defects or fractures caused by ageing, trauma and tumour resection is still a great challenge in clinical treatment. Although autologous bone graft is considered as gold standard, the source of natural bone is limited. In recent years, regenerative therapy based on bioactive materials has been proposed for bone reconstruction. Specially, numerous studies have indicated that bioactive ceramics including silicate and phosphate bioceramics exhibit excellent osteoinductivity and osteoconductivity, further promote bone regeneration. In addition, magnesium (Mg) element, as an indispensable mineral element, plays a vital role in promoting bone mineralisation and formation. In this review, different types of Mg-containing bioceramics including Mg-containing calcium phosphate-based bioceramics (such as Mg-hydroxyapatite, Mg-biphasic calcium phosphate), Mg-containing calcium silicate-based bioceramics (such as Mg2SiO4, Ca2MgSi2O7 and Mg-doped bioglass), Mg-based biocements, Mg-containing metal/polymer-bioceramic composites were systematacially summarised. Additionally, the fabrication technologies and their materiobiological effects were deeply discussed. Clinical applications and perspectives of magnesium-containing bioceramics for bone repair are highlighted. Overall, Mg-containing bioceramics are regarded as regenerative therapy with their optimised performance. Furthermore, more in-depth two-way researches on their performance and structure are essential to satisfy their clinical needs.

Heterogeneous DNA hydrogel loaded with Apt02 modified tetrahedral framework nucleic acid accelerated critical-size bone defect repair.

Segmental bone defects, stemming from trauma, infection, and tumors, pose formidable clinical challenges. Traditional bone repair materials, such as autologous and allogeneic bone grafts, grapple with limitations including source scarcity and immune rejection risks. The advent of nucleic acid nanotechnology, particularly the use of DNA hydrogels in tissue engineering, presents a promising solution, attributed to their biocompatibility, biodegradability, and programmability. However, these hydrogels, typically hindered by high gelation temperatures (∼46 °C) and high construction costs, limit cell encapsulation and broader application. Our research introduces a novel polymer-modified DNA hydrogel, developed using nucleic acid nanotechnology, which gels at a more biocompatible temperature of 37 °C and is cost-effective. This hydrogel then incorporates tetrahedral Framework Nucleic Acid (tFNA) to enhance osteogenic mineralization. Furthermore, considering the modifiability of tFNA, we modified its chains with Aptamer02 (Apt02), an aptamer known to foster angiogenesis. This dual approach significantly accelerates osteogenic differentiation in bone marrow stromal cells (BMSCs) and angiogenesis in human umbilical vein endothelial cells (HUVECs), with cell sequencing confirming their targeting efficacy, respectively. In vivo experiments in rats with critical-size cranial bone defects demonstrate their effectiveness in enhancing new bone formation. This innovation not only offers a viable solution for repairing segmental bone defects but also opens avenues for future advancements in bone organoids construction, marking a significant advancement in tissue engineering and regenerative medicine.

Dual-network DNA-silk fibroin hydrogels with controllable surface rigidity for regulating chondrogenic differentiation.

Osteoarthritis (OA) is a common joint disease known for cartilage degeneration, leading to a substantial burden on individuals and society due to its high disability rate. However, current clinical treatments for cartilage defects remain unsatisfactory due to the unclear mechanisms underlying cartilage regeneration. Tissue engineering hydrogels have emerged as an attractive approach in cartilage repair. Recent research studies have indicated that stem cells can sense the mechanical strength of hydrogels, thereby regulating their differentiation fate. In this study, we present the groundbreaking construction of dual-network DNA-silk fibroin (SF) hydrogels with controllable surface rigidity. The supramolecular networks, formed through DNA base-pairing, induce the development of ß-sheet structures by constraining and aggregating SF molecules. Subsequently, SF was cross-linked via horseradish peroxidase (HRP)-mediated enzyme reactions to form the second network. Experimental results demonstrated a positive correlation between the surface rigidity of dual-network DNA-SF hydrogels and the DNA content. Interestingly, it was observed that dual-network DNA-SF hydrogels with moderate surface rigidity exhibited the highest effectiveness in facilitating the migration of bone marrow mesenchymal stem cells (BMSCs) and their chondrogenic differentiation. Transcriptome sequencing further confirmed that dual-network DNA-SF hydrogels primarily enhanced chondrogenic differentiation of BMSCs by upregulating the Wnt and TGF-ß signaling pathways while accelerating collagen II synthesis. Furthermore, in vivo studies revealed that dual-network DNA-SF hydrogels with moderate surface rigidity significantly accelerated cartilage regeneration. In summary, the dual-network DNA-SF hydrogels represent a promising and novel therapeutic strategy for cartilage regeneration.

SrHPO4-coated Mg alloy implant attenuates postoperative pain by suppressing osteoclast-induced sensory innervation in osteoporotic fractures.

Osteoporotic fractures have become a common public health problem and are usually accompanied by chronic pain. Mg and Mg-based alloys are considered the next-generation orthopedic implants for their excellent osteogenic inductivity, biocompatibility, and biodegradability. However, Mg-based alloy can initiate aberrant activation of osteoclasts and modulate sensory innervation into bone callus resulting in postoperative pain at the sequential stage of osteoporotic fracture healing. Its mechanism is going to be investigated. Strontium hydrogen phosphate (SrHPO4) coating to delay the Mg-based alloy degradation, can reduce the osteoclast formation and inhibit the growth of sensory nerves into bone callus, dorsal root ganglion hyperexcitability, and pain hypersensitivity at the early stage. Liquid chromatography-mass spectrometry (LC-MS) metabolomics analysis of bone marrow-derived macrophages (BMMs) treated with SrHPO4-coated Mg alloy extracts shows the potential effect of increased metabolite levels of AICAR (an activator of the AMPK pathway). We demonstrate a possible modulated secretion of AICAR and osteoclast differentiation from BMMs, which inhibits sensory innervation and postoperative pain through the AMPK/mTORc1/S6K pathway. Importantly, supplementing with AICAR in Mg-activated osteoclasts attenuates postoperative pain. These results suggest that Mg-induced postoperative pain is related to the osteoclastogenesis and sensory innervation at the early stage in the osteoporotic fractures and the SrHPO4 coating on Mg-based alloys can reduce the pain by upregulating AICAR secretion from BMMs or preosteoclasts.

Second near-infrared photoactivatable nanomedicines for enhanced photothermal-chemodynamic therapy of cancer.

Nanomedicines have been widely used for cancer therapy, while controlling their activity for effective and safe treatment remains a big challenge. Herein, we report the development of a second near-infrared (NIR-II) photoactivatable enzyme-loaded nanomedicine for enhanced cancer therapy. Such a hybrid nanomedicine contains a thermoresponsive liposome shell loaded with copper sulfide nanoparticles (CuS NPs) and glucose oxidase (GOx). The CuS nanoparticles mediate the generation of local heat under 1064 nm laser irradiation, which not only can be used for NIR-II photothermal therapy (PTT), but also leads to the destruction of the thermal-responsive liposome shell to achieve the on-demand release of CuS nanoparticles and GOx. In a tumor microenvironment, GOx oxidizes glucose to produce hydrogen peroxide (H2O2) that acts as a medium to promote the efficacy of chemodynamic therapy (CDT) by CuS nanoparticles. This hybrid nanomedicine enables the synergetic action of NIR-II PTT and CDT to obviously improve efficacy without remarkable side effects via NIR-II photoactivatable release of therapeutic agents. Such a hybrid nanomedicine-mediated treatment can achieve complete ablation of tumors in mouse models. This study provides a promising nanomedicine with photoactivatable activity for effective and safe cancer therapy.

Icaritin ameliorates RANKL-mediated osteoclastogenesis and ovariectomy-induced osteoporosis.

A rapidly aging society and longer life expectancy are causing osteoporosis to become a global epidemic. Over the last five decades, a number of drugs aimed at reducing bone resorption or restoring bone mass have been developed, but their efficacy and safety are limited. Icaritin (ICT) is a natural compound extracted from anti-osteoporosis herb Epimedium spp. and has been shown to inhibit osteoclast differentiation. However, the molecular mechanism by which ICT weaken RANKL-induced osteoclast differentiation has not been completely investigated. Here, we evaluated the anti-osteoclastogenic effect of ICT in vitro and the potential drug candidate for treating osteoporosis in vivo. In vitro study, ICT was found to inhibit osteoclast formation and bone resorption function via downregulating transcription factors activated T cell cytoplasm 1 (NFATc1) and c-fos, which further downregulate osteoclastogenesis-specific gene. In addition, the enhanced mitochondrial mass and function required for osteoclast differentiation was mitigated by ICT. The histomorphological results from an in vivo study showed that ICT attenuated the bone loss associated with ovariectomy (OVX). Based on these results, we propose ICT as a promising new drug strategy for osteoporosis that inhibits osteoclast differentiation.

Ultrasound-triggered in situ gelation with ROS-controlled drug release for cartilage repair.

Cartilage defects are usually caused by acute trauma and chronic degeneration. However, it is still a great challenge to improve the repair of articular cartilage defects due to the limited self-regeneration capacity of such defects. Herein, a novel ROS-responsive in situ nanocomposite hydrogel loaded with kartogenin (KGN) and bone marrow-derived stem cells (BMSCs) was designed and constructed via the enzymatic reaction of fibrinogen and thrombin. Meanwhile, a ROS-responsive thioketal (TK)-based liposome was synthesized to load the chondrogenesis-inducing factor KGN, the bioenzyme thrombin and an ultrasound-sensitive agent PpIX. Under ultrasound stimulation, the TK-based liposome was destroyed, followed by in situ gelation of fibrinogen and thrombin. Moreover, sustained release of KGN was realized by regulating the ultrasound conditions. Importantly, ROS generation and KGN release within the microenvironment of the in situ fibrin hydrogel significantly promoted chondrogenic differentiation of BMSCs via the Smad5/mTOR signalling pathway and effectively improved cartilage regeneration in a rat articular cartilage defect model. Overall, the novel in situ nanocomposite hydrogel with ROS-controlled drug release has great potential for efficient cartilage repair.

Exosome-Laden Hydrogels: A Novel Cell-free Strategy for In-situ Bone Tissue Regeneration.

In-situ bone tissue regeneration, which harnesses cell external microenvironment and their regenerative potential to induce cell functions and bone reconstruction through some special properties of biomaterials, has been deeply developed. In which, hydrogel was widely applied due to its 3D network structure with high water absorption and mimicking native extracellular matrix (ECM). Additionally, exosomes can participate in a variety of physiological processes such as cell differentiation, angiogenesis and tissue repair. Therefore, a novel cell-free tissue engineering (TE) using exosome-laden hydrogels has been explored and developed for bone regeneration in recent years. However, related reviews in this field are limited. Therefore, we elaborated on the shortcomings of traditional bone tissue engineering, the challenges of exosome delivery and emphasized the advantages of exosome-laden hydrogels for in-situ bone tissue regeneration. The encapsulation strategies of hydrogel and exosomes are listed, and the research progress and prospects of bioactive hydrogel composite system for continuous delivery of exosomes for in-situ bone repair are also discussed in this review.

Research Progress of Exosomes in Bone Diseases: Mechanism, Diagnosis and Therapy.

With the global escalation of the aging process, the number of patients with bone diseases is increasing year by year. Currently, there are limited effective treatments for bone diseases. Exosome, as a vital medium in cell-cell communication, can mediate tissue metabolism through the paracrine transmission of various cargos (proteins, nucleic acids, lipids, etc.) carried by itself. Recently, an increasing number of researchers have proven that exosomes play essential roles in the formation, metabolism, and pathological changes of bone and cartilage. Because exosomes have the advantages of small size, rich sources, and low immunogenicity, they can be used not only as substitutes for the traditional treatment of bone diseases, but also as biomarkers for the diagnosis of bone diseases. This paper reviews the research progress of several kinds of cells derived-exosomes in bone diseases and provides a theoretical basis for further research and clinical application of exosomes in bone diseases in the future.

Carnosol inhibits osteoclastogenesis in vivo and in vitro by blocking the RANKL­induced NF­κB signaling pathway.

Bone homeostasis is maintained by osteoclast-mediated bone resorption and osteoblast­mediated bone formation. Disruption of bone homeostasis due to excessive osteoclastogenesis or reduced osteogenesis results in various disorders, such as postmenopausal osteoporosis. Receptor activator of NF­κB ligand (RANKL) stimulation of the NF­κB signaling pathway is essential in osteoclastogenesis. The aim of the present study was to investigate the novel effects of carnosol, an active compound found in Rosmarinus officinalis, on RANKL­induced osteoclastogenesis both in vitro and in vivo. TRAP staining showed that carnosol significantly inhibited osteoclasts differentiation of bone marrow monocytes and RAW264.7 cells. Western blot results showed that the protein expression levels of osteoclastogenesis­associated genes, including cathepsin K, tartrate­resistant acid phosphatase and MMP­9, were markedly inhibited by carnosol, which may have suppressed osteoclast function. Furthermore, western blot and immunofluorescent staining results revealed that carnosol markedly suppressed the phosphorylation of p65 induced by RANKL and blocked its nuclear translocation, indicating the suppression of NF­κB signaling pathway. H&E staining and micro­CT results showed that in vivo treatment with carnosol significantly attenuated ovariectomy­induced bone loss in mice. In conclusion, the present study indicated that carnosol may suppress osteoclastogenesis both in vivo and in vitro by inhibiting the activation of the NF­κB signaling pathway. Carnosol may therefore be a potential novel therapeutic candidate for the clinical treatment of osteoclast­related disorders.

Effects of urolithin A on osteoclast differentiation induced by receptor activator of nuclear factor-κB ligand via bone morphogenic protein 2.

Urolithin A (UA) is an intestinal microbial metabolite derived from ellagitannins and a promising agent for treating osteoarthritis. However, its effects on osteoporosis are unclear. This study explored the effects of urolithin A (UA) on receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclasts and its underlying molecular mechanisms. RANKL treatment significantly increased tartrate-resistant acid phosphatase (TRACP) or osteoclast marker levels (P < 0.05), while adding UA decreased the RANKL-induced levels (P < 0.05) in RAW264.7 cells. Total RNA isolated from RANKL- or RANKL + UA-treated cells was sequenced, and the obtained transcriptome dataset revealed 2,399 differentially expressed genes. They were enriched in multiple pathways involved in rheumatoid arthritis, ERK1 and ERK2 cascade, regulation of inflammatory response, ECM-receptor interactions, and TNF signaling. Scanning electron microscopy showed that RANKL promoted bone resorption pits in bone biopsy specimens, whereas UA inhibited their formation. When bone morphogenic protein 2 (BMP2) was shRNA-silenced, the bone resorption pits were restored. Moreover, while RANKL significantly enhanced the levels of p-ERK2/ERK2, p-p38/p38, p-Akt1/Akt1, p-ERK1/ERK1, and osteoclast-related proteins (P < 0.05), UA reduced them. BMP2 silencing also reversed the UA inhibitory effect. Thus, UA represses the RANKL-induced osteoclast differentiation of RAW264.7 cells by regulating Akt1, p38, and ERK1/2 signaling, and BMP2 likely reverses the UA inhibitory effect via these pathways. We propose BMP2 as a potential drug target for treating bone metabolic diseases, such as osteoporosis.

Antibody-conjugated gold nanoparticles as nanotransducers for second near-infrared photo-stimulation of neurons in rats.

Infrared neural stimulation with the assistance of photothermal transducers holds great promise as a mini-invasive neural modulation modality. Optical nanoparticles with the absorption in the near-infrared (NIR) window have emerged as excellent photothermal transducers due to their good biocompatibility, surface modifiability, and tunable optical absorption. However, poor activation efficiency and limited stimulation depth are main predicaments encountered in the neural stimulation mediated by these nanoparticles. In this study, we prepared a targeted polydopamine (PDA)-coated gold (Au) nanoparticles with specific binding to thermo-sensitive ion channel as nanotransducers for second near-infrared (NIR-II) photo-stimulation of neurons in rats. The targeted Au nanoparticles were constructed via conjugation of anti-TRPV1 antibody with PEGylated PDA-coated Au nanoparticles and thus exhibited potent photothermal performance property in the second NIR (NIR-II) window and converted NIR-II light to heat to rapidly activate Ca2+ influx of neurons in vitro. Furthermore, wireless photothermal stimulation of neurons in living rat successfully evoke excitation in neurons in the targeted brain region as deep as 5 mm beneath cortex. This study thus demonstrates a remote-controlled strategy for neuromodulation using photothermal nanotransducers.