Neglecting Bone Health: A Critical Gap in Management of Muscle Spasticity with Botulinum Toxin in Spinal Cord Injury.

Neuromuscular inhibitors have been quickly advanced from being used only for aesthetic purposes to being used as a treatment for musculoskeletal pain and muscle spasticity. This phenomenon stems from the diminished force exerted by muscles, which are essential for bone remodeling. In this context, it is hypothesized that botulinum toxin (BTX) might exert a direct influence on bone resorption. Although such treatments have the potential to provide patients with significant relief, bone loss occurring due to elective muscle paralysis has yet to be examined in clinical trials. The disuse model resulting from spinal cord injury, characterized by the absence of ground reaction and muscle forces, provides an ideal context for exploring the skeletal ramifications of intramuscular BTX injection. This approach enables an investigation into the intricate interplay between muscle and bone, encompassing the impact of spasticity on bone preservation, the potential positive and negative outcomes of BTX on bone metabolism, and the involvement of the autonomic nervous system in bone remodeling regulation. This paper presents a narrative review of research findings on the disturbance of the typical balance between muscles and bones caused by acute muscle paralysis from BTX, resulting in osteopenia and bone resorption.

Bone scaffolds-based localized drugs delivery for osteosarcoma: current status and future perspective.

A common malignant bone neoplasm in teenagers is Osteosarcoma. Chemotherapy, surgical therapy, and radiation therapy together comprise the usual clinical course of treatment for Osteosarcoma. While Osteosarcoma and other bone tumors are typically treated surgically, however, surgical resection frequently fails to completely eradicate tumors, and in turn becomes the primary reason for postoperative recurrence and metastasis, ultimately leading to a high rate of mortality. Patients still require radiation and/or chemotherapy after surgery to stop the spread of the tumor and its metastases, and both treatments have an adverse influence on the body's organ systems. In the postoperative management of osteosarcoma, bone scaffolds can load cargos (growth factors or drugs) and function as drug delivery systems (DDSs). This review describes the different kinds of bone scaffolds that are currently available and highlights key studies that use scaffolds as DDSs for the treatment of osteosarcomas. The discussion also includes difficulties and perspectives regarding the use of scaffold-based DDSs. The study may serve as a source for outlining efficient and secure postoperative osteosarcoma treatment plans.

Bone targeted nano-drug and nano-delivery.

There are currently no targeted delivery systems to satisfactorily treat bone-related disorders. Many clinical drugs consisting of small organic molecules have a short circulation half-life and do not effectively reach the diseased tissue site. This coupled with repeatedly high dose usage that leads to severe side effects. With the advance in nanotechnology, drugs contained within a nano-delivery device or drugs aggregated into nanoparticles (nano-drugs) have shown promises in targeted drug delivery. The ability to design nanoparticles to target bone has attracted many researchers to develop new systems for treating bone related diseases and even repurposing current drug therapies. In this review, we shall summarise the latest progress in this area and present a perspective for future development in the field. We will focus on calcium-based nanoparticle systems that modulate calcium metabolism and consequently, the bone microenvironment to inhibit disease progression (including cancer). We shall also review the bone affinity drug family, bisphosphonates, as both a nano-drug and nano-delivery system for bone targeted therapy. The ability to target and release the drug in a controlled manner at the disease site represents a promising safe therapy to treat bone diseases in the future.

Salidroside: A Promising Agent in Bone Metabolism Modulation.

Rhodiola rosea, a long-lived herbaceous plant from the Crassulaceae group, contains the active compound salidroside, recognized as an adaptogen with significant therapeutic potential for bone metabolism. Salidroside promotes osteoblast proliferation and differentiation by activating critical signaling pathways, including bone morphogenetic protein-2 and adenosine monophosphate-activated protein kinase, essential for bone formation and growth. It enhances osteogenic activity by increasing alkaline phosphatase activity and mineralization markers, while upregulating key regulatory proteins including runt-related transcription factor 2 and osterix. Additionally, salidroside facilitates angiogenesis via the hypoxia-inducible factor 1-alpha and vascular endothelial growth factor pathway, crucial for coupling bone development with vascular support. Its antioxidant properties offer protection against bone loss by reducing oxidative stress and promoting osteogenic differentiation through the nuclear factor erythroid 2-related factor 2 pathway. Salidroside has the capability to counteract the negative effects of glucocorticoids on bone cells and prevents steroid-induced osteonecrosis. Additionally, it exhibits multifaceted anti-inflammatory actions, notably through the inhibition of tumor necrosis factor-alpha and interleukin-6 expression, while enhancing the expression of interleukin-10. This publication presents a comprehensive review of the literature on the impact of salidroside on various aspects of bone tissue metabolism, emphasizing its potential role in the prevention and treatment of osteoporosis and other diseases affecting bone physiology.

Interventional Effect of Donkey Bone Collagen Peptide Iron Chelate on Cyclophosphamide Induced Immunosuppressive Mice.

Immunodeficiency can disrupt normal physiological activity and function. In this study, donkey bone collagen peptide (DP) and its iron chelate (DPI) were evaluated their potential as immunomodulators in cyclophosphamide (Cytoxan®, CTX)-induced Balb/c mice. The femoral tissue, lymphocytes, and serum from groups of mice were subjected to hematoxylin and eosin (H&E) staining, methylthiazolyldiphenyl-tetrazolium bromide (MTT) cell proliferation assays, and enzyme-linked immunosorbent assay (ELISA), respectively. Furthermore, a non-targeted metabolomics analysis based on UPLC-MS/MS and a reverse transcription polymerase chain reaction (RT-qPCR) technology were used to explore the specific metabolic pathways of DPI regulating immunocompromise. The results showed that CTX was able to significantly reduce the proliferative activity of mouse splenic lymphocytes and led to abnormal cytokine expression. After DP and DPI interventions, bone marrow tissue damage was significantly improved. In particular, DPI showed the ability to regulate the levels of immune factors more effectively than Fe2+ and DP. Furthermore, metabolomic analysis in both positive and negative ion modes showed that DPI and DP jointly regulated the levels of 20 plasma differential metabolites, while DPI and Fe2+ jointly regulated 14, and all 3 jointly regulated 10. Fe2+ and DP regulated energy metabolism and pyrimidine metabolism pathways, respectively. In contrast, DPI mainly modulated the purine salvage pathway and the JAK/STAT signaling pathway, which are the key to immune function. Therefore, DPI shows more effective immune regulation than Fe2+ and DP alone, and has good application potential in improving immunosuppression.

Combining three-dimensionality and CaP glass-PLA composites: Towards an efficient vascularization in bone tissue healing.

Bone regeneration often fails due to implants/grafts lacking vascular supply, causing necrotic tissue and poor integration. Microsurgical techniques are used to overcome this issue, allowing the graft to anastomose. These techniques have limitations, including severe patient morbidity and current research focuses on stimulating angiogenesis in situ using growth factors, presenting limitations, such as a lack of control and increased costs. Non-biological stimuli are necessary to promote angiogenesis for successful bone constructs. Recent studies have reported that bioactive glass dissolution products, such as calcium-releasing nanoparticles, stimulate hMSCs to promote angiogenesis and new vasculature. Moreover, the effect of 3D microporosity has also been reported to be important for vascularisation in vivo. Therefore, we used room-temperature extrusion 3D printing with polylactic acid (PLA) and calcium phosphate (CaP) based glass scaffolds, focusing on geometry and solvent displacement for scaffold recovery. Combining both methods enabled reproducible control of 3D structure, porosity, and surface topography. Scaffolds maintained calcium ion release at physiological levels and supported human mesenchymal stem cell proliferation. Scaffolds stimulated the secretion of vascular endothelial growth factor (VEGF) after 3 days of culture. Subcutaneous implantation in vivo indicated good scaffold integration and blood vessel infiltration as early as one week after. PLA-CaP scaffolds showed increased vessel maturation 4 weeks after implantation without vascular regression. Results show PLA/CaP-based glass scaffolds, made via controlled 3D printing, support angiogenesis and vessel maturation, promising improved vascularization for bone regeneration.

Graded Modulation of Inflammation by Metal Ion-Coordinated Peptide-Based Hydrogel Chemical Regulators Promotes Tendon-Bone Junction Regeneration.

After rotator cuff injuries, uncontrolled inflammation hinders tendon-bone junction regeneration and induces scar formation in situ. Therefore, precisely controlling inflammation could be a solution to accelerate tendon-bone junction regeneration. In this study, we synthesized a peptide-metal ion complex hydrogel with thermosensitive capability that can be used as a hydrogel chemical regulator. By the coordination complex between Mg2+ and BMP-12, the free and coordinated Mg2+ can be programmability released from the hydrogel. The fast release of free Mg2+ can prevent inflammation at the early stage of injuries, according to the results of RT-qPCR and immunofluorescence staining. Then, the coordinated Mg2+ was slowly released from the hydrogel and provided an anti-inflammatory environment for tendon-bone junction regeneration in the long term. Finally, the hydrogel demonstrated enhanced therapeutic effects in a rat rotator cuff tear model. Overall, the Mg2+/BMP-12 peptide-metal ion complex-based hydrogel effectively addresses the regenerative requirements of the tendon-bone junction across various stages by graded modulating inflammation.

Employing novel biocompatible composite scaffolds with bioglass 58S and poly L-lactic acid for effective bone defect treatment.

BACKGROUND: Bioglass materials have gained significant attention in the field of tissue engineering due to their osteoinductive and biocompatible properties that promote bone cell differentiation. In this study, a novel composite scaffold was developed using a sol-gel technique to combine bioglass (BG) 58 S with a poly L-lactic acid (PLLA). METHODS AND RESULTS: The physiochemical properties, morphology, and osteoinductive potential of the scaffolds were investigated by X-ray diffraction analysis, scanning electron microscopy, and Fourier-transform infrared spectroscopy. The results showed that the SiO2-CaO-P2O5 system was successfully synthesized by the sol-gel method. The PLLA scaffolds containing BG was found to be osteoinductive and promoted mineralization, as demonstrated by calcium deposition assay, upregulation of alkaline phosphatase enzyme activity, and Alizarin red staining data. CONCLUSIONS: These in vitro studies suggest that composite scaffolds incorporating hBMSCs are a promising substitute material to be implemented in bone tissue engineering. The PLLA/BG scaffolds promote osteogenesis and support the differentiation of bone cells, such as osteoblasts, due to their osteoinductive properties.

Tianhe Zhuifeng Gao reverses inflammatory response and attenuates bone/cartilage destruction in rheumatoid arthritis via PSMC2-RUNX2-COL1A1 axis based on transcriptional regulatory network analysis and experimental validation.

BACKGROUND: Tianhe Zhuifeng Gao (TZG) is an authorized Chinese patent drug with satisfying clinical efficacy, especially for RA patients with cold-dampness syndrome. However, its underlying pharmacological mechanisms remain unclear. METHOD: Anti-arthritic effects of TZG were evaluated using an adjuvant-induced arthritis (AIA) rat model. Transcriptional regulatory network analysis based on synovial tissues obtained from AIA rats, combining with our previous analysis based on whole blood samples from RA patients with cold-dampness syndrome and co-immunoprecipitation were performed to identify involved dominant pathways, which were experimentally verified using AIA-wind-cold-dampness stimulation modified (AIA-M) animal model. RESULTS: TZG treatment dramatically attenuated joint injury and inflammatory response in AIA rats, and PSMC2-RUNX2-COL1A1 axis, which was closely associated with bone/cartilage damage, was inferred to be one of therapeutic targets of TZG against RA. Experimentally, TZG displayed obvious pharmacological effects for alleviating the joint inflammation and destruction through reinstating the body weight, reducing the arthritis score, the limbs diameters, the levels of RF and CRP, and the inflammatory cytokines, recovering the thymus and spleen indexes, diminishing bone and cartilage destruction, as well elevating the pain thresholds of AIA-M rats. In addition, TZG markedly reversed the abnormal energy metabolism in AIA-M rats through enhancing articular temperature, daily water consumption, and regulating expression levels of energy metabolism parameters and hormones. Moreover, TZG also significantly modulated the abnormal expression levels of PSMC2, RUNX2 and COL1A1 proteins in the ankle tissues of AIA-M rats. CONCLUSION: TZG may exert the bone protective effects in RA therapy via regulating bone and cartilage damage-associated PSMC2-RUNX2-COL1A1 axis.

Bioactive material­sodium alginate-polyvinyl alcohol composite film scaffold for bone tissue engineering application.

Road accidents and infection-causing diseases during bone surgery are serious problems in orthopedics, and thus, addressing these pressing challenges is crucial. In the present study, the 70S30C calcium silicate bioactive material (BM) is synthesized by a sustainable approach employing a precipitation method using recycled rice husk and eggshells as a precursor of silica and calcium. Further, 70S30C BM is composited with sodium alginate (SA) and polyvinyl alcohol (PVA), and the films were prepared by solvent casting method. The composite films were prepared without the addition of acid, binder, and crosslinking agents. Further, the films were characterized by BET, XRD, ATR-FTIR, SEM, and EDS mapping. The in vitro bioactivity and biodegradation study is performed in the simulated body fluid (SBF). The in vitro haemolysis study is executed using human blood and the results demonstrate haemocompatibility of the composite films. The ex ovo CAM assay also exhibits good neovascularization. The in vitro and in vivo biocompatibility assay proves its non-toxic nature. Further, the in vivo study reveals that the engineered composite film demonstrates accelerated osteogenesis. This work broadens the orthopedic potential of the composite film and offers bioactivity, haemocompatibility, angiogenesis, non-toxicity, and in vivo osteogenesis which would serve as a potential candidate for bone tissue engineering application.

Oral Administration of Deer Bone Collagen Peptide Can Enhance the Skin Hydration Ability and Antioxidant Ability of Aging Mice Induced by D-Gal, and Regulate the Synthesis and Degradation of Collagen.

Skin problems caused by aging have attracted much attention, and marine collagen peptides have been proved to improve these problems, while mammalian collagen peptides are rarely reported. In this study, fermented deer bone collagen peptide (FCP) and non-fermented deer bone collagen peptide (NCP) were extracted from fermented and non-fermented deer bone, respectively, and their peptide sequences and differential proteins were analyzed using LC-MS/MS technology. After they were applied to aging mice induced with D-gal, the skin hydration ability, antioxidant ability, collagen synthesis, and degradation ability of the mice were studied. The results show that FCP and NCP are mainly peptides that constitute type Ⅰ collagen, and their peptide segments are different. In vivo experiments show that FCP and NCP can improve the richness of collagen fibers in the skin of aging mice; improve the hydration ability of skin; promote the activity of antioxidant-related enzymes; and also show that through the TGF-ß and MAPK pathways, the synthesis and degradation of collagen in skin are regulated. These results show that deer bone collagen peptide can improve skin problems caused by aging, promote skin hydration and antioxidant capacity of aging mice, and regulate collagen synthesis and degradation through the MAPK pathway.

[Determination of the presence of an antibiotic in implant-bone biopsy specimens by Raman spectroscopy in experiment]. / Opredelenie nalichiya antibiotika v implantato-kostnykh bioptatakh metodom ramanovskoi spektroskopii v eksperimente.

THE AIM OF THE STUDY: Was to determine the presence of an amoxicillin-based antibiotic in bone implant biopsies by Raman spectroscopy in an experiment. MATERIALS AND METHODS: Experimental animals (n=10, a miniature pig of the Svetlogorsk breed) were divided into 2 groups of 5 animals. Groups 1 and 2 were injected with amoxicillin 2 ml per 20 kg of body weight 30 minutes before dental implantation surgery, then group 2 was additionally injected with 1 ml per 20 kg of body weight for 5 days. Each animal has 6 implants installed. On the 1st, 3rd, 7th, 14th day, an implant-bone biopsy was removed from each animal, micro-preparations were made and Raman spectroscopy was performed to assess the peak matching of the Raman spectrum. RESULTS: In animals of the 1st and 2nd groups, the main peak of the Raman spectrum, which is closest to the values of the antibiotic spectrum of interest to us, is located closer to 1448 cm-1 and 1446 cm-1, respectively. At the same time, in both observations, the peaks relate to the spectrum of bone tissue, which cannot indicate the content of an antibiotic in the drug. CONCLUSION: No scattering spectra corresponding to the antibiotic molecule were found in any animal from both groups, regardless of the mode of administration and dosage of amoxicillin. The detected peaks corresponded to bone tissue without an antibiotic.

Nutraceuticals and Functional Foods: A Comprehensive Review of Their Role in Bone Health.

Bone health is the result of a tightly regulated balance between bone modeling and bone remodeling, and alterations of these processes have been observed in several diseases both in adult and pediatric populations. The imbalance in bone remodeling can ultimately lead to osteoporosis, which is most often associated with aging, but contributing factors can already act during the developmental age, when over a third of bone mass is accumulated. The maintenance of an adequate bone mass is influenced by genetic and environmental factors, such as physical activity and diet, and particularly by an adequate intake of calcium and vitamin D. In addition, it has been claimed that the integration of specific nutraceuticals such as resveratrol, anthocyanins, isoflavones, lycopene, curcumin, lutein, and ß-carotene and the intake of bioactive compounds from the diet such as honey, tea, dried plums, blueberry, and olive oil can be efficient strategies for bone loss prevention. Nutraceuticals and functional foods are largely used to provide medical or health benefits, but there is an urge to determine which products have adequate clinical evidence and a strong safety profile. The aim of this review is to explore the scientific and clinical evidence of the positive role of nutraceuticals and functional food in bone health, focusing both on molecular mechanisms and on real-world studies.

Photocrosslinked gelatin/chondroitin sulfate/chitosan-based composites with tunable multifunctionality for bone tissue regeneration.

Novel hydrogel-based multifunctional systems prepared utilizing photocrosslinking and freeze-drying processes (PhotoCross/Freeze-dried) dedicated for bone tissue regeneration are presented. Fabricated materials, composed of methacrylated gelatin, chitosan, and chondroitin sulfate, possess interesting features including bioactivity, biocompatibility, as well as antibacterial activity. Importantly, their degradation and swellability might be easily tuned by playing with the biopolymeric content in the photocrosllinked systems. To broaden the potential application and deliver the therapeutic features, mesoporous silica particles functionalized with methacrylate moieties decorated with hydroxyapatite and loaded with the antiosteoporotic drug, alendronate, (MSP-MA-HAp-ALN) were dispersed within the biopolymeric sol and photocrosslinked. It was demonstrated that the obtained composites are characterized by a significantly extended degradation time, ensuring optimal conditions for balancing hybrids removal with the deposition of fresh bone. We have shown that attachment of MSP-MA-HAp-ALN to the polymeric matrix minimizes the initial burst effect and provides a prolonged release of ALN (up to 22 days). Moreover, the biological evaluation in vitro suggested the capability of the resulted systems to promote bone remodeling. Developed materials might potentially serve as scaffolds that after implantation will fill up bone defects of various origin (osteoporosis, tumour resection, accidents) providing the favourable conditions for bone regeneration and supporting the infections' treatment.

Protective Role of Nanoceria-Infused Nanofibrous Scaffold toward Bone Tissue Regeneration with Senescent Cells.

The presence of oxidative stress in bone defects leads to delayed regeneration, especially in the aged population and patients receiving cancer treatment. This delay is attributed to the increased levels of reactive oxygen species (ROS) in these populations due to the accumulation of senescent cells. Tissue-engineered scaffolds are emerging as an alternative method to treat bone defects. In this study, we engineered tissue scaffolds tailored to modulate the adverse effects of oxidative stress and promote bone regeneration. We used polycaprolactone to fabricate nanofibrous mats by using electrospinning. We exploited the ROS-scavenging properties of cerium oxide nanoparticles to alleviate the high oxidative stress microenvironment caused by the presence of senescent cells. We characterized the nanofibers for their physical and mechanical properties and utilized an ionization-radiation-based model to induce senescence in bone cells. We demonstrate that the presence of ceria can modulate ROS levels, thereby reducing the level of senescence and promoting osteogenesis. Overall, this study demonstrates that ceria-infused nanofibrous scaffolds can be used for augmenting the osteogenic activity of senescent progenitor cells, which has important implications for engineering bone tissue scaffolds for patients with low regeneration capabilities.

Hydroxyapatite Nanoparticles Promote the Development of Bone Microtissues for Accelerated Bone Regeneration by Activating the FAK/Akt Pathway.

Scaffold-free bone microtissues differentiated from mesenchymal stem cell (MSC) spheroids offer great potential for bottom-up bone tissue engineering as a direct supply of cells and osteogenic signals. Many biomaterials or biomolecules have been incorporated into bone microtissues to enhance their osteogenic abilities, but these materials are far from clinical approval. Here, we aimed to incorporate hydroxyapatite (HAP) nanoparticles, an essential component of bone matrix, into MSC spheroids to instruct their osteogenic differentiation into bone microtissues and further self-organization into bone organoids with a trabecular structure. Furthermore, the biological interaction between HAP nanoparticles and MSCs and the potential molecular mechanisms in the bone development of MSC spheroids were investigated by both in vitro and in vivo studies. As a result, improved cell viability and osteogenic abilities were observed for the MSC spheroids incorporated with HAP nanoparticles at a concentration of 30 µg/mL. HAP nanoparticles could promote the sequential expression of osteogenic markers (Runx2, Osterix, Sclerostin), promote the expression of bone matrix proteins (OPN, OCN, and Collagen I), promote the mineralization of the bone matrix, and thus promote the bone development of MSC spheroids. The differentiated bone microtissues could further self-organize into linear, lamellar, and spatial bone organoids with trabecular structures. More importantly, adding FAK or Akt inhibitors could decrease the level of HAP-induced osteogenic differentiation of bone microtissues. Finally, excellent new bone regeneration was achieved after injecting bone microtissues into cranial bone defect models, which could also be eliminated by the Akt inhibitor. In conclusion, HAP nanoparticles could promote the development of bone microtissues by promoting the osteogenic differentiation of MSCs and the formation and mineralization of the bone matrix via the FAK/Akt pathway. The bone microtissues could act as individual ossification centers and self-organize into macroscale bone organoids, and in this meaning, the bone microtissues could be called microscale bone organoids. Furthermore, the bone microtissues revealed excellent clinical perspectives for injectable cellular therapies for bone defects.

High circulating concentrations of estradiol are anabolic for bone mass and strength in an adult male to female transgender mouse model.

The effects of gender affirming hormone therapy (GAHT) on bone microarchitecture and fracture risk in adult transgender women is unclear. To investigate the concept that skeletal integrity and strength in trans women may be improved by treatment with a higher dose of GAHT than commonly prescribed, we treated adult male mice with a sustained, high dose of estradiol. Adult male mice at 16 weeks of age were administered ~1.3 mg estradiol by silastic implant, implanted intraperitoneally, for 12 weeks. Controls included vehicle treated intact females and males. High-dose estradiol treatment in males stimulated the endocortical deposition of bone at the femoral mid-diaphysis, increasing cortical thickness and bone area. This led to higher stiffness, maximum force, and the work required to fracture the bone compared to male controls, while post-yield displacement was unaffected. Assessment of the material properties of the bone showed an increase in both elastic modulus and ultimate stress in the estradiol treated males. Treatment of male mice with high dose estradiol was also anabolic for trabecular bone, markedly increasing trabecular bone volume, number and thickness in the distal metaphysis which was accompanied by an increase in the histomorphometric markers of bone remodelling, mineralizing surface/bone surface, bone formation rate and osteoclast number. In conclusion, a high dose of estradiol is anabolic for cortical and trabecular bone in a male to female transgender mouse model, increasing both stiffness and strength. These findings suggest that increasing the current dose of GAHT administered to trans women, while considering other potential adverse effects, may be beneficial to preserving their bone microstructure and strength.

Alendronate/lactoferrin-dual decorated lipid nanocarriers for bone-homing and active targeting of ivermectin and methyl dihydrojasmonate for leukemia.

Chronic myeloid leukemia is a hematological cancer, where disease relapse and drug resistance are caused by bone-hosted-residual leukemia cells. An innovative resolution is bone-homing and selective-active targeting of anticancer loaded-nanovectors. Herein, ivermectin (IVM) and methyl dihydrojasmonate (MDJ)-loaded nanostructured lipid carriers (IVM-NLC) were formulated then dually decorated by lactoferrin (Lf) and alendronate (Aln) to optimize (Aln/Lf/IVM-NLC) for active-targeting and bone-homing potential, respectively. Aln/Lf/IVM-NLC (1 mg) revealed nano-size (73.67 ± 0.06 nm), low-PDI (0.43 ± 0.06), sustained-release of IVM (62.75 % at 140-h) and MDJ (78.7 % at 48-h). Aln/Lf/IVM-NLC afforded substantial antileukemic-cytotoxicity on K562-cells (4.29-fold lower IC50), higher cellular uptake and nuclear fragmentation than IVM-NLC with acceptable cytocompatibility on oral-epithelial-cells (as normal cells). Aln/Lf/IVM-NLC effectively upregulated caspase-3 and BAX (4.53 and 15.9-fold higher than IVM-NLC, respectively). Bone homing studies verified higher hydroxyapatite affinity of Aln/Lf/IVM-NLC (1 mg; 22.88 ± 0.01 % at 3-h) and higher metaphyseal-binding (1.5-fold increase) than untargeted-NLC. Moreover, Aln/Lf/IVM-NLC-1 mg secured 1.35-fold higher in vivo bone localization than untargeted-NLC, with lower off-target distribution. Ex-vivo hemocompatibility and in-vivo biocompatibility of Aln/Lf/IVM-NLC (1 mg/mL) were established, with pronounced amelioration of hepatic and renal toxicity compared to higher Aln doses. The innovative Aln/Lf/IVM-NLC could serve as a promising nanovector for bone-homing, active-targeted leukemia therapy.

Two Weeks of Continuous Opioid Treatment in an Adenine-Induced Mouse Model of Chronic Kidney Disease Exacerbates the Bone Inflammatory State and Increases Osteoclasts.

Patients with chronic kidney disease (CKD) report high pain levels, but reduced renal clearance eliminates many analgesic options; therefore, 30-50% of CKD patients have chronic opioid prescriptions. Opioid use in CKD is associated with higher fracture rates. Opioids may directly alter bone turnover directly through effects on bone cells and indirectly via increasing inflammation. We hypothesized that continuous opioid exposure would exacerbate the high bone turnover state of CKD and be associated with elevated measures of inflammation. Male C57Bl/6J mice after 8 weeks of adenine-induced CKD (AD) and non-AD controls (CON) had 14-day osmotic pumps (0.25-µL/hr release) containing either saline or 50-mg/mL oxycodone (OXY) surgically implanted in the subscapular region. After 2 weeks, all AD mice had elevated blood urea nitrogen, parathyroid hormone, and serum markers of bone turnover compared to controls with no effect of OXY. Immunohistochemical staining of the distal femur showed increased numbers of osteocytes positive for the mu opioid and for toll-like receptor 4 (TLR4) due to OXY. Osteocyte protein expression of tumor necrosis factor-α (TNF-α) and RANKL were higher due to both AD and OXY so that AD + OXY mice had the highest values. Trabecular osteoclast-covered surfaces were also significantly higher due to both AD and OXY, resulting in AD + OXY mice having 4.5-fold higher osteoclast-covered surfaces than untreated CON. These data demonstrate that opioids are associated with a pro-inflammatory state in osteocytes which increases the pro-resorptive state of CKD.