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Although bone marrow and bone toxicities have been reported in breast cancer survivors, preventative strategies are yet to be developed. Clinical studies suggest consumption of long chain omega-3 polyunsaturated fatty acids (LCn3PUFA) can attenuate age-related bone loss, and recent animal studies also revealed benefits of LCn3PUFA in alleviating bone marrow and bone toxicities associated with methotrexate chemotherapy. Using a female rat model for one of the most commonly used anthracycline-containing breast cancer chemotherapy regimens (adriamycin + cyclophosphamide) (AC) chemotherapy, this study investigated potential effects of daily LCn3PUFA consumption in preserving bone marrow and bone microenvironment during chemotherapy. AC treatment for four cycles significantly reduced bone marrow cellularity and increased marrow adipocyte contents. It increased trabecular bone separation but no obvious changes in bone volume or bone cell densities. LCn3PUFA supplementation (375 mg/100 g/day) attenuated AC-induced bone marrow cell depletion and marrow adiposity. It also partially attenuated AC-induced increases in trabecular bone separation and the cell sizes and nuclear numbers of osteoclasts formed ex vivo from bone marrow cells isolated from AC-treated rats. This study suggests that LCn3PUFA supplementation may have beneficial effects in preventing bone marrow damage and partially protecting the bone during AC cancer chemotherapy.

Radiotherapy is essential to cancer treatment, while it inevitably injures surrounding normal tissues, and bone tissue is one of the most common sites prone to irradiation. Bone marrow mesenchymal stem cells (BMMSCs) are sensitive to irradiation and the irradiated dysfunction of BMMSCs may be closely related to irradiation-induced bone damage. Macropahges play important role in regulating stem cell function, bone metabolic balance and irradiation response, but the effects of macrophages on irradiated BMMSCs are still unclear. This study aimed to investigate the role of macrophages and macrophage-derived exosomes in restoring irradiated BMMSCs function. The effects of macrophage conditioned medium (CM) and macrophage-derived exosomes on osteogenic and fibrogenic differentiation capacities of irradiated BMMSCs were detected. The key microribonucleic acids (miRNAs) and targeted proteins in exosomes were also determined. The results showed that irradiation significantly inhibited the proliferation of BMMSCs, and caused differentiation imbalance of BMMSCs, with decreased osteogenic differentiation and increased fibrogenic differentiation. M2 macrophage-derived exosomes (M2D-exos) inhibited the fibrogenic differentiation and promoted the osteogenic differentiation of irradiated BMMSCs. We identified that miR-142-3p was significantly overexpressed in M2D-exos and irradiated BMMSCs treated with M2D-exos. After inhibition of miR-142-3p in M2 macrophage, the effects of M2D-exos on irradiated BMMSCs differentiation were eliminated. Furthermore, transforming growth factor beta 1 (TGF-β1), as a direct target of miR-142-3p, was significantly decreased in irradiated BMMSCs treated with M2D-exos. This study indicated that M2D-exos could carry miR-142-3p to restore the differentiation balance of irradiated BMMSCs by targeting TGF-β1. These findings pave a new way for promising and cell-free method to treat irradiation-induced bone damage.

Due to rapid urbanization and industrialization, Cadmium (Cd) contamination is widespread. Meanwhile, the prevalence of nonalcoholic fatty liver disease (NAFLD) has been increasing. Cd is linked to bone damage. However, the osteotoxicity of environmental Cd exposure in NAFLD remains unclear. Therefore, this study aimed to investigate the effects and potential mechanisms of Cd on bone metabolism in NAFLD mice. NAFLD mice were treated with 50 mg/L cadmium chloride in drinking water for 12 weeks. Bone microstructures were scanned by Micro-CT. Liver lipid droplets and fibrosis were measured by histopathological staining. Insulin tolerance tests were performed in mice. RT-PCR and Western blot were performed to analyse hepatic inflammation factors. Results show no damage in healthy mice exposed to Cd. However, Cd exacerbated liver fibrosis and significantly reduced cancellous bone mineral density and decreased the number and thickness of trabecular bone in NAFLD mice. Additionally, the morphology of trabecular bone transformed from a plate structure to a rod structure in NAFLD mice after Cd exposure. The underlying mechanism appears to be related to the Cd-induced direct or indirect toxicity. Exacerbated liver fibrosis, increased inflammatory factors (TGF-β and IL-1β), and reduced lecithin-cholesterol acyltransferase (LCAT) and insulin-like growth factor-1 (IGF-1) might contribute to bone damages. Collectively, our study illustrates that despite lower dosing Cd exposure did not induce bone damages in healthy mice, Cd caused bone loss in NAFLD mice. Therefore, it is recommended that individuals with metabolic disorders should avoid working in Cd pollution environment and consuming cadmium-contaminated food and water.

Xanthohumol (XAN) is an isoprenyl flavonoid from Humulus lupulus L. known for beer brewing, and an osteoprotective agent due to its active improvement in bone loss of osteoporosis. This study was first time to investigate its effects on anti-gouty bone injury in rats of gouty arthritis (GA) induced by monosodium urate (MSU). Results showed that XAN could significantly exert anti-inflammatory activity by alleviating swelling degree of joints, reducing serum level of inflammatory factors, improving inflammatory injury and degrading the Markin’s score in lesion joint. Meanwhile, XAN could also fight against gouty bone damage by improving pathological changes of bone tissue and parameters of bone micro-structure. Moreover, XAN could even promote bone formation by effectively enhancing expression of Runx2 and OPG, while inhibit bone resorption with depressing matrix metalloproteinase-9 (MMP-9), MMP-13 and CTSK expression, reducing RANKL secretion, and abating the ratio of RANKL/OPG. Therefore, it was the first time to reveal the mechanism of XAN against gouty bone injury via inhibiting RANKL/OPG/RANK signaling pathway. Above all, this study provided potential strategy for the treatment of GA, and further contributed to research and resource development for hops.

Background Thioacetamide (TAA) is used in various fields, such as synthetic drugs, organic chemical synthesis, and materials chemistry. TAA is mainly used to establish animal liver injury models and other organ damage models to explore their mechanisms for helping patients with liver disease. Liver damage can lead to abnormal expression of some enzymes in the serum, so we detected the appropriate enzyme levels in the serum of SD rats to verify the damage of TAA to the liver. More importantly, TAA caused bone damage is barely understood. Therefore, our research aims to establish a rat model reflecting the acute bone damage injury caused by TAA. Methods The SD rats were intraperitoneally injected with normal saline (0.9%) or TAA (200 mg/kg, 400 mg/kg) for 1 month (once the other day). After the last intraperitoneal injection, serum samples from rats were used for biochemical tests. Masson staining is used to detect liver damage, and micro-CT is used to detect the changes in bone. Moreover, the three-point bending experiment was used to detect the force range of the hind limbs of SD rats. Results Compared with the control group, after the intraperitoneal injection of TAA, the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), uric acid (UA), total bile acid (TBA), alkaline phosphatase (ALP), carbamide (UREA) and creatinine (CREA) rose sharply, while the levels of serum content of total protein (TP), lactate dehydrogenase (LDH), calcium (Ca) and phosphorus (P) were severely reduced. After TAA administration, collagen fibers were deposited and liver fibrosis was obvious. Micro-CT results showed that the bone surface, tissue surface, bone volume, and tissue volume of rats with an intraperitoneal injection of TAA were significantly reduced. In addition, the bones of rats with an intraperitoneal injection of TAA can resist less pressure and are prone to fractures. Conclusions TAA can cause liver damage in SD rats, which is explained by the changes in serum biochemical indicators and the deposition of liver collagen. More importantly, TAA can reduce bone mineral density and increase the separation of bone trabeculae in SD rats, and finally lead to bone injury. This suggests that TAA may become an ideal model to investigate abnormal bone metabolism after liver injury.

Osteotomy is a common step in oncological, reconstructive, and trauma surgery. Drilling and elevated temperature during osteotomy produce thermal osteonecrosis. Heat and associated mechanical damage during osteotomy can impair bone healing, with consequent failure of fracture fixation or dental implants. Several ex vivo studies on animal bone were recently focused on heating production during osteotomy with conventional drill and piezoelectric devices, particularly in endosseous dental implant sites. The current literature on bone drilling and osteotomic surface analysis is here reviewed and the dynamics of bone healing after osteotomy with traditional and piezoelectric devices are discussed. Moreover, the methodologies involved in the experimental osteotomy and clinical studies are compared, focusing on ex vivo and in vivo findings.

The investigation of bone damage processes is a crucial point to understand the mechanisms of age-related bone fractures. In order to reduce their impact, early diagnosis is key. The intricate architecture of bone and the complexity of multiscale damage processes make fracture prediction an ambitious goal. This review, supported by a detailed analysis of bone damage physical principles, aims at presenting a critical overview of how multiscale imaging techniques could be used to implement reliable and validated numerical tools for the study and prediction of bone fractures. While macro- and meso-scale imaging find applications in clinical practice, micro- and nano-scale imaging are commonly used only for research purposes, with the objective to extract fragility indexes. Those images are used as a source for multiscale computational damage models. As an example, micro-computed tomography (micro-CT) images in combination with micro-finite element models could shed some light on the comprehension of the interaction between micro-cracks and micro-scale bone features. As future insights, the actual state of technology suggests that these models could be a potential substitute for invasive clinical practice for the prediction of age-related bone fractures. However, the translation to clinical practice requires experimental validation, which is still in progress.

Spinal tuberculosis (STB) is a common form of extrapulmonary tuberculosis (ETB). However, the molecular mechanism of pathological injury in STB remains unclear. The purpose of this study was to explore the pathogenic mechanism of STB, and compare it with (E.coli) bone infections and lumbar degenerative disease (LDD) patients. In this study, the infected lumbar spine bone tissue of STB patients was collected for the infection group. LDD patients and E.coli lumbar spine infection (SEcoli) patients were collected for the non-M.TB infection group. Proteins from the bone tissue were extracted for 4D-Label Free Proteomics (4D-LFQ) analysis to compare the pathogenesis and immune mechanisms of STB and SEcoli. The osteoclast growth inhibitory factors tumor necrosis factor receptor superfamily member 11B (TNFRSF11B) and semaphorin-3A (Sema3A) were significantly down-regulated in STB, while the protein Wnt-5a (WNT5A) secreted by osteoblasts was significantly up-regulated. These changes in STB bone metabolism may lead to an increase in the number of osteoclasts and bone injury. In addition, the significantly up-regulated expression of thymocyte selection-related family member 2 (THEMIS2) suggests that THEMIS2 may be a potential therapeutic target for STB that could control the Toll-like receptor response of macrophages. Meanwhile, the PI3K-Atk anti-apoptotic pathway and the ECM-receptor interaction pathway were inhibited during both infections. This study explored the pathogenic mechanism of STB based on proteomics and compared its differences with E.coli bone infection, providing new insight into the treatment of STB.

Bone disease associated with multiple myeloma (MM) is characterized by osteolytic lesions and pathological fractures, which remain a therapeutic priority despite new drugs improving MM patient survival. Antiresorptive molecules represent the main option for the treatment of MM-associated bone disease (MMBD), whereas osteoanabolic molecules are under investigation. Among these latter, we here focused on the myokine irisin, which is able to enhance bone mass in healthy mice, prevent bone loss in osteoporotic mouse models, and accelerate fracture healing in mice. Therefore, we investigated irisin effect on MMBD in a mouse model of MM induced by intratibial injection of myeloma cells followed by weekly administration of 100 μg/kg of recombinant irisin for 5 wk. By micro-Ct analysis, we demonstrated that irisin improves MM-induced trabecular bone damage by partially preventing the reduction of femur Trabecular Bone Volume/Total Volume (P = .0028), Trabecular Number (P = .0076), Trabecular Fractal Dimension (P = .0044), and increasing Trabecular Separation (P = .0003) in MM mice. In cortical bone, irisin downregulates the expression of Sclerostin, a bone formation inhibitor, and RankL, a pro-osteoclastogenic molecule, while in BM it upregulates Opg, an anti-osteoclastogenic cytokine. We found that in the BM tibia of irisin-treated MM mice, the percentage of MM cells displays a reduction trend, while in the femur it decreases significantly. This is in line with the in vitro reduction of myeloma cell viability after 48 h of irisin stimulation at both 200 and 500 ng/mL and, after 72 h already at 100 ng/mL rec-irisin. These results could be due to irisin ability to downregulate the expression of Notch 3, which is important for cell-to-cell communication in the tumor niche, and Cyclin D1, supporting an inhibitory effect of irisin on MM cell proliferation. Overall, our findings suggest that irisin could be a new promising strategy to counteract MMBD and tumor burden in one shot. Lay Summary Multiple myeloma (MM) is a hematologic malignancy characterized by uncontrolled proliferation of a plasma cell clone in the BM. The main clinical complication of MM is represented by Bone Disease (BD) often determining pathological fractures and increased mortality risk. To date, MMBD treatment is based on molecules able to avoid bone resorption, but many patients continue to fracture; thus, molecules involved in new bone deposition are under investigation. Among these, we focused on irisin, produced by skeletal muscle during physical exercise, which is able to enhance bone mass and accelerate fracture healing in mice, and prevent bone loss in osteoporotic mice. Therefore, by using a mouse model of MM, we demonstrated that irisin improves MM-induced trabecular bone damage, downregulates the expression of the inhibitor of bone formation, Sclerostin, and modulates bone resorption molecules in favor of bone protection. We also found that irisin reduces MM cell invasion in the femoral BM of mice and reduces myeloma cell viability in vitro, presumably by irisin ability to downregulate the expression of Notch 3 and the regulator of cell proliferation Cyclin D1. Overall, our findings suggest that irisin could be a new promising strategy to counteract MMBD and tumor burden in one shot. Graphical Abstract Graphical Abstract We thank Servier Medical Art (https://smart.servier.com/) for providing free image software to build the figure.

Chronic cases of chikungunya fever represent a public health problem in countries where the virus circulates. The disease is prolonged, in some cases, for years, resulting in disabling pain and bone erosion among other bone and joint problems. As time progresses, tissue damage is persistent, although the virus has not been found in blood or joints. The pathogenesis of these conditions has not been fully explained. Additionally, it has been considered that there are multiple factors that might intervene in the viral pathogenesis of the different conditions that develop. Other mechanisms involved in osteoarthritic diseases of non-viral origin could help explain how damage is produced in chronic conditions. The aim of this review is to analyze the molecular and cellular factors that could be involved in the tissue damage generated by different infectious conditions of the chikungunya virus.