Bone Resorption Process Research Articles

Utility of bone turnover markers in metabolic bone diseases

Bone turnover markers (BTMs) are biochemical indicators that provide information about the rate of bone remodeling, which involves the continuous process of bone formation and bone resorption. BTMs are measured in blood or urine samples and are used in the diagnosis, monitoring, and management of various metabolic bone diseases. They aid in the diagnosis of metabolic bone diseases by providing information about the bone turnover status. Abnormal levels of BTMs can indicate increased bone resorption or decreased bone formation, which are characteristic of certain conditions such as osteoporosis, osteomalacia, or Paget's disease. BTMs can provide insights into the severity of metabolic bone diseases. For example, in osteoporosis, elevated levels of bone resorption markers such as C-terminal telopeptide of type I collagen (CTX) or tartrate-resistant acid phosphatase 5b (TRACP-5b) indicate increased bone breakdown and higher fracture risk. Similarly, low levels of bone formation markers like procollagen type I N-terminal propeptide (PINP) or osteocalcin can indicate reduced bone formation and decreased bone strength. BTMs are valuable tools for assessing the response to treatment in metabolic bone diseases. Changes in BTM levels over time can indicate the effectiveness of interventions such as pharmacotherapy, lifestyle modifications, or surgical interventions. Decreased levels of bone resorption markers or increased levels of bone formation markers suggest a positive response to treatment, whereas persistent abnormal BTM levels may indicate the need for treatment adjustment. It's important to note that BTMs should be interpreted in conjunction with other clinical factors and imaging studies. They provide valuable information about bone turnover dynamics but should not be relied upon as standalone diagnostic or prognostic tools.

Bioactive elements manipulate bone regeneration.

While bone tissue is known for its inherent regenerative abilities, various pathological conditions and trauma can disrupt its meticulously regulated processes of bone formation and resorption. Bone tissue engineering aims to replicate the extracellular matrix of bone tissue as well as the sophisticated biochemical mechanisms crucial for effective regeneration. Traditionally, the field has relied on external agents like growth factors and pharmaceuticals to modulate these processes. Although efficacious in certain scenarios, this strategy is compromised by limitations such as safety issues and the transient nature of the compound release and half-life. Conversely, bioactive elements such as zinc (Zn), magnesium (Mg) and silicon (Si), have garnered increasing interest for their therapeutic benefits, superior stability, and reduced biotic risks. Moreover, these elements are often incorporated into biomaterials that function as multifaceted bioactive components, facilitating bone regeneration via release on-demand. By elucidating the mechanistic roles and therapeutic efficacy of the bioactive elements, this review aims to establish bioactive elements as a robust and clinically viable strategy for advanced bone regeneration.

Effect of α-Mangostin on Interleukin-11 and Runt-related Transcription Factor-2 Gene Expression on Cell Line Osteoblast Cultures Induced with Lipopolysaccharide.

Loss of permanent teeth after tooth extraction without replacement of missing teeth can result in impaired masticatory, esthetic, phonetic functions, and impaired balance of the masticatory organ in the mouth. Therefore, a method is needed to inhibit the alveolar bone resorption process so that the dimensions of the tooth socket can be maintained vertically or horizontally until the time of implant placement, which is called the socket preservation procedure. α-mangostin is known to have a potential anti-inflammatory effect and most likely can be used as a potential therapeutic agent to inhibit bone resorption caused by posttooth extraction inflammatory processes. The aim of the study was to determine the effect on the inflammatory process and osteogenesis on osteoblast cell line culture by induction with lipopolysaccharide (LPS) and α-mangostin. This was an in vitro laboratory experimental study on mouse osteoblast cell line culture. The treatment was given with LPS, α-mangostin, and combination on osteogenic medium, using the same concentration for all concentrates. The sample will then be processed and analyzed using the real-time polymerase chain reaction. The highest interleukin-11 (IL-11) gene expression was found in α-mangostin treatment, but there was no significant difference in IL-11 expression between the study groups. The highest runt-related transcription factor-2 (RUNX-2) gene expression was found in a group that received induction with LPS and α-mangostin, and from these results, it was found that there was a significant difference in RUNX-2 expression between the study groups. LPS and α-mangostin can increase osteogenesis in osteoblast cell culture in the osteogenic medium.

Impact of Exercises on Bone Health of Pre-Menopausal Female

The process of bone resorption and creation, in which osteoclasts destroy old bone and osteoblasts produce new bone, causes the living tissue of bone to continually degrade. Bone is a dynamic tissue that adjusts to the accompanying mechanical forces that are put on it, such as exercise. In order to lower the risk of osteoporosis and resultant fractures during the postmenopausal years, with relative-risk rises, it is crucial to maintain appropriate bone mineral density (BMD) levels throughout the premenopausal years. Pre-menopausal women have been found to have osteopenia and osteoporosis at prevalence rates of 15% and 0.6%, respectively [1]. In addition, it has been found that premenopausal women lose between 0.25 and 1% of their bone mineral density per year [2]. In Pakistan, the long-life expectancy after menopause, multiparity, lack of a calcium-rich diet, vitamin D deficiency, physical inactivity, as well as socio-demographic factors, all contribute to an increase in the prevalence of primary, type II osteoporosis and its associated complications. According to a local survey, it affects postmenopausal women 20-49.3% of the time [3]. Although pre-menopausal women are often unsuitable for pharmaceutical treatment, relying on lifestyle factors is virtually always advised. Exercise, a low-cost, non-pharmacologic intervention that is accessible to the great majority of the population, is one potentially successful lifestyle strategy for accomplishing this aim. During youth, exercise improves bone growth and increases BMD, and it may help older people avoid osteoporosis and fractures. Regular exercise, particularly weight-bearing and high-impact exercises, helps the body build high peak bone mass and may lower the risk of falls and osteoporotic fractures in later life. Regarding femoral neck BMD, high-impact exercise was shown to be most beneficial, and it has also been hypothesized that gains brought on by high-impact exercise are retained after intervention. In healthy pre-menopausal women, high-impact exercise increases the bone mineral density in the upper femur and the lumbar spine. This kind of exercise could be an effective, secure, and affordable strategy to prevent osteoporosis later in life if done regularly. Progressive resistance strength training for the lower limbs is the kind of exercise that have the greatest impact on BMD for the neck of the femur and should be taken into consideration in clinical practice. The multicomponent training exercise programme has been recommended as the most effective intervention for BMD at the spine. Aerobic exercises involving weight bearing and training on vibrating platforms may also improve BMD.

Selective estrogen receptor modulators in post-menopausal osteoporosis

Osteoporosis (OP) is a chronic disease that occurs when the balance between the processes of bone formation and resorption is lost. OP is characterized by a decrease in bone quality and an increased risk of fractures. In post-menopausal women, as a result of decreased estrogen levels, there is bone loss. Hormone replacement therapy was initially used for the management of OP in post-menopausal women but was soon abandoned due to the occurrence of significant side effects. This shifted research toward the development of a class of drugs called selective estrogen receptor modulators (SERMs). These drugs always act through estrogen receptors (ERs), but as agonists or antagonists depending on the tissue under consideration. In particular, SERMs at the level of bone tissue behave as agonists of ERs but, as they do not result in the occurrence of estrogen side effects, they are widely used in the therapy of post-menopausal OP. This review provides a brief summary of the characteristics of SERMs employed in the treatment of post-menopausal OP.

Characteristics of the state of bone tissue in genetically modified mice with impaired enzymatic regulation of steroid hormone metabolism

Introduction: The aim was to evaluate the structural and functional changes of bone tissue in mice with null expression of 11β-HSD2 or both 11β-HSD2 and Apolipoprotein E.
 Materials and methods: The experimental study was performed in 60 male mice, weighting 24–30 g. The animals were kept in accordance with the rules of laboratory practice for preclinical studies on the territory of the Russian Federation. Mice lacking 11β-HSD2 (Hsd2-/-) and male mice lacking 11β-HSD2 and Apolipoprotein E (Hsd2-/-/Apoe-/-) were used in the study. We studied and characterized the state of bone tissue, indicators of bone density, microcircu­lation in bone tissue, endothelial dysfunction coefficient, width of bone trabeculae, as well as serum concentrations of bone alkaline phosphatase, hydroxyproline, deoxyprinoline and expression levels of p53, Bcl2, Bax, eNOS genes.
 Results and discussion: We showed that mice with the Hsd2-/- genotype with no expression of 11ß-HSD2 by the 6th month of life showed a statistically significant decrease in bone density, which progresses to the 7th and 8th months of life. At the 8th month of animal life, a decrease in bone density is accompanied by a statistically significant decrease in the level of microcirculation in the bone and an increase in the coefficient of endothelial dysfunction. Taking into account the relationship of endothelial dysfunction, atherogenesis and disorders in the processes of bone remodeling, in the framework of this study, we also assessed the state of bone tissue in double transgenes with the genotype Hsd2-/-/Apoe-/-, which lack the expression of both 11ß-HSD2 and Apolipoprotein E. In this study, we also saw increased acti­vation of processes leading to disruption of bone remodeling processes. In the group of the animals with the genotype Hsd2-/-/Apoe-/-, we found statistically significant differences from the mice with no expression of 11ß-HSD2 in bone density and microcirculation, and the width of bone trabeculae. Also, a statistically significant increase in hydroxypro­line and deoxyprinoline was found in the group of double transgenes, in the absence of significant changes in the con­centration of bone alkaline phosphatase. This fact indicates a pronounced activation of bone resorption processes in the absence of activation of osteosynthesis processes, which leads to the detected violation of bone remodeling processes.
 Conclusion: Thus, we have shown that a violation of the metabolic regulation of steroid hormone metabolism in ani­mals with null expression of the 11ß-HSD2 (Hsd2-/- genotype) leads to the development of signs of osteoporosis – bone density decreases, which is accompanied by a decrease in the width of bone trabeculae, the level of microcirculation in bone tissue decreases simultaneously with an increase in the coefficient of endothelial dysfunction. The additional null expression of ApoE gene in double transgenes with the genotype Hsd2-/-/Apoe-/- leads to an increase in the severity of changes associated with a violation of bone remodeling processes and, in addition to a more pronounced change in bone tissue density, bone trabecular width, microcirculation and the coefficient of endothelial dysfunction leads to an increase in the concentration of biochemical markers of bone resorption. These changes indicate the important role of the enzyme 11ß-hydroxysteroid dehydrogenase type 2 in the processes of bone remodeling disorders.
 Graphical abstract:

Role of G protein-associated membrane receptors in the pathogenesis of osteoporosis

Osteoporosis is a chronic disease characterized by a pathological change in bone tissue, excessive fragility and a decrease in bone strength as a result of the predominance of bone resorption processes over the process of bone formation. This disease manifests in the form of low-traumatic fractures occurring in result of falling from a height of one’s height, or with little physical exertion. Osteoporosis could result in the fractures of the vertebral bodies and bones of the peripheral skeleton, causing a high level of disability. Of note, postmenopausal osteoporosis develops in women against the background of the cessation of the menstrual cycle. Here we overview the role of G-protein-associated membrane receptors (GPCR family) in the pathogenesis of this disease and the prospects for finding targets among these receptors for the diagnosis and treatment of osteoporosis. Malformations in the genes encoding GPCR lead to impaired bone tissue remodeling. Exploring the functions of GPCR family members is critical to the search for predisposition markers of bone tissue dysfunction and could improve the early diagnosis of osteoporosis. Studies on a model of osteoblasts differentiated from hIPSCs obtained from patients with osteoporosis associated with mutations in the genes of the GPCR family will allow a deeper understanding of the molecular nature of osteoporosis and the identification of new targets for osteoporosis treatment.

Impact of the host response and osteoblast lineage cells on periodontal disease

Periodontitis involves the loss of connective tissue attachment and alveolar bone. Single cell RNA-seq experiments have provided new insight into how resident cells and infiltrating immune cells function in response to bacterial challenge in periodontal tissues. Periodontal disease is induced by a combined innate and adaptive immune response to bacterial dysbiosis that is initiated by resident cells including epithelial cells and fibroblasts, which recruit immune cells. Chemokines and cytokines stimulate recruitment of osteoclast precursors and osteoclastogenesis in response to TNF, IL-1β, IL-6, IL-17, RANKL and other factors. Inflammation also suppresses coupled bone formation to limit repair of osteolytic lesions. Bone lining cells, osteocytes and periodontal ligament cells play a key role in both processes. The periodontal ligament contains cells that exhibit similarities to tendon cells, osteoblast-lineage cells and mesenchymal stem cells. Bone lining cells consisting of mesenchymal stem cells, osteoprogenitors and osteoblasts are influenced by osteocytes and stimulate formation of osteoclast precursors through MCSF and RANKL, which directly induce osteoclastogenesis. Following bone resorption, factors are released from resorbed bone matrix and by osteoclasts and osteal macrophages that recruit osteoblast precursors to the resorbed bone surface. Osteoblast differentiation and coupled bone formation are regulated by multiple signaling pathways including Wnt, Notch, FGF, IGF-1, BMP, and Hedgehog pathways. Diabetes, cigarette smoking and aging enhance the pathologic processes to increase bone resorption and inhibit coupled bone formation to accelerate bone loss. Other bone pathologies such as rheumatoid arthritis, post-menopausal osteoporosis and bone unloading/disuse also affect osteoblast lineage cells and participate in formation of osteolytic lesions by promoting bone resorption and inhibiting coupled bone formation. Thus, periodontitis involves the activation of an inflammatory response that involves a large number of cells to stimulate bone resorption and limit osseous repair processes.

Role of sclrostin (SOST) to predisposing for osteoporosis in β- thalassemia major patients

Sclrostin is a biomarker interrupted in bone resorption process by binding to LRP5 and/or LRP6 family, and prevent Wingless-type signaling (Wnt) which is important to both bone development and the maintain of bone mass. Sixty (60) patients with thalassemia major were enrolled from the period 2/5/2021 to 1/9/2021 in summer to assessment role of sclrostin to predisposing for osteoporosis in β-thalassemia major patients (β-TM). Patients ages were from (2-40 year) males and females they divided to children and adults had osteoporosis and/or osteopenia."All patients diagnosed by Hb electrophoresis and were receiving regular blood transfusions for anemia and chelation therapy for prevention of iron overload related complications. Detailed history and examination including height and weight were recorded on pre-designed questionnaire and blood samples were taken for measurement of serum"sclrostin level. The results showed non-significant differences (P˃0.05) of serum sclerostin (SOST) concentration between osteoporosis of beta thalassemia patients (β-TM) and osteopenia of beta thalassemia patients for both gender, but appeared increased significant (P˃0.05) in male adults of osteopenia with progressive aged.

Cathepsin K: A Versatile Potential Biomarker and Therapeutic Target for Various Cancers.

Cancer, a common malignant disease, is one of the predominant causes of diseases that lead to death. Additionally, cancer is often detected in advanced stages and cannot be radically cured. Consequently, there is an urgent need for reliable and easily detectable markers to identify and monitor cancer onset and progression as early as possible. Our aim was to systematically review the relevant roles of cathepsin K (CTSK) in various possible cancers in existing studies. CTSK, a well-known key enzyme in the bone resorption process and most studied for its roles in the effective degradation of the bone extracellular matrix, is expressed in various organs. Nowadays, CTSK has been involved in various cancers such as prostate cancer, breast cancer, bone cancer, renal carcinoma, lung cancer and other cancers. In addition, CTSK can promote tumor cells proliferation, invasion and migration, and its mechanism may be related to RANK/RANKL, TGF-β, mTOR and the Wnt/β-catenin signaling pathway. Clinically, some progress has been made with the use of cathepsin K inhibitors in the treatment of certain cancers. This paper reviewed our current understanding of the possible roles of CTSK in various cancers and discussed its potential as a biomarker and/or novel molecular target for various cancers.

Peculiarities of bone tissue metabolism in patients with acute otitis media with impared carbonhydrate metabolism

Introductions: Relevance of the study is due to the unrecognized effect of carbohydrate metabolism disorders on bone tissue metabolism in patients with acute otitis media (AOM). Aim: to determine the peculiarities of bone tissue metabolism in patients with AOM caused by disorders of carbohydrate metabolism. Materials and methods: Our study included 73 patients aged 18 to 79 (29 males and 44 females) who were randomized into 4 groups according to the aim of the research: Group 1 – 17 patients with AOM, Group 2 – 15 patients with AOM combined with paranasal sinus pathology, Group 3 – 20 patients with AOM on the background of type 2 diabetes mellitus, Group 4 – 21 patients with AOM combined with transitory disorders of glucose metabolism. On the basis of clinical examination all patients were tested for glycosylated hemoglobin (HbAlc), blood calcium level and parathormone as a marker of bone resorption and osteocalcin as a marker of bone remodeling. Results of the study and discussion: The statistical evaluation of the indicators identified a reliable difference between groups 1-2 and groups 3-4, while between groups 1 and 2, 3 and 4 reliable difference in metabolic parameters of bone tissue has not been established. The level of glucosylated hemoglobin was significantly elevated even for transitory signs of carbohydrate metabolism disorders (5,17±0,17%, 4,95±0,17%, 9,8±0,46% and 7,78±0,19% in groups 1,2, 3 and 4 respectively).The value of parathormone was within the reference values, but it proved to be significantly (p˂0,001) higher in glucose metabolism disorders (56.8±3.02pg/ml and 52.56±2.7pg/ml in groups 3 and 4, respectively).The amount of osteocalcin and calcium tended to decrease in type 2 diabetes mellitus (group 3) and in transitory disorders (group 4), but without a significant difference (p˃0.05). Correlation analysis revealed a strong correlation between glucose and glucosylated hemoglobin levels in patients in group 3 and the average strength in patients in group 4 (r=0.832 and r=0.44, respectively). The increase of parathormone level on the basis of carbohydrate metabolism disorders was due to the presence of correlation with the level of glucosylated haemoglobin in groups 3 and 4 (r=0.705 and r=0.81 respectively). Calcium correlations of r=-0.77 and r=-0.56 with parathormone level and r=-0.79 and r=-0.44 with glucosylated haemoglobin level were found in patients of groups 3 and 4 accordingly. In the absence of glucose metabolism disorders in groups 1 and 2, no significant correlations were found, except for physiologically determined correlations of parathormone and calcium levels in group 1 (r=-0.489). Conclusions: Disorders of carbohydrate metabolism negatively affect metabolism of bone tissue due to activation of bone resorption processes. This is manifested by correlated with the level of glycosylated hemoglobin by an increase in the amount of parathormone with pathogenetic significance of both type 2 diabetes mellitus and transitory disorders of carbohydrate metabolism.In this category of patients, the level of parathormone and its dynamics, as well as the determination of glucosylated hemoglobin are informative even in transitory disorders of carbohydrate metabolism.

Ca2+-activated chloride channel ANO1: A new regulator of osteoclast function

A paper by Sun et al. identified the Ca2+-activated Cl− channel anoctamin 1 or ANO1 (TMEM16A) as an important regulator of osteoclast function by interacting with RANKL activating signaling pathways involved in bone resorption. Although Cl− transporters (e.g. ClC7, CLIC5) have been known to be involved in the active process of bone resorption, ANO1 appears to control osteoclast differentiation and function to levels beyond those of other Cl−transporters. Regulating ANO1 function might be a useful target for therapeutics in osteoporosis.

Comparative analysis of dental micromobility at the stages of orthodontic dental protrusion treatment in patients with healthy periodontium and generalized periodontitis of moderate severity

BACKGROUND: Literature data revealed that the prevalence of periodontal diseases in all age groups is high, at 90%95%. The inflammatory processes in the periodontal tissues have a multifactorial nature. The application of a small force while correcting dentofacial anomalies and deformities is necessary to achieve the desired results and to preserve physiological processes in the periodontium in case of bone resorption and alveolar process bone formation at the stages of correction.
 AIM: To assess dental mobility dynamics according to periotestometry data in patients with chronic generalized periodontitis of moderate severity and protrusion of the anterior teeth at the stages of orthodontic treatment.
 MATERIAL AND METHODS: A total of 70 patients aged 3544 years with generalized periodontitis of moderate severity, complete dentition, absence of orthopedic structures, and protrusion of incisors without general somatic diseases were examined and treated. Dental micromobility was assessed using the periotest apparatus prior to orthodontic treatment, at the stage of eliminating gaps and after removing the bracket system.
 RESULTS: The dental micromobility increased after the application of the braces, but in group 2 with generalized periodontitis of moderate severity, it was by 2.67 times higher. Anterior teeth position stabilization lead to a gradual decrease (stabilization) in periotestometry indicators. In group 2 b using a low-force traction, this process was more intensive.
 CONCLUSION: The dynamics of periotestometry indicators at the stages of orthodontic treatment of dental protrusion in the presence of generalized periodontitis of moderate severity indicates the formation of favorable conditions in the periodontium for the mobility of the teeth using low-force traction.

Roles of osteoclasts in alveolar bone remodeling.

Osteoclasts are large multinucleated cells from hematopoietic origin and are responsible for bone resorption. A balance between osteoclastic bone resorption and osteoblastic bone formation is critical to maintain bone homeostasis. The alveolar bone, also called the alveolar process, is the part of the jawbone that holds the teeth and supports oral functions. It differs from other skeletal bones in several aspects: its embryonic cellular origin, the form of ossification, and the presence of teeth and periodontal tissues; hence, understanding the unique characteristic of the alveolar bone remodeling is important to maintain oral homeostasis. Excessive osteoclastic bone resorption is one of the prominent features of bone diseases in the jaw such as periodontitis. Therefore, inhibiting osteoclast formation and bone resorptive process has been the target of therapeutic intervention. Understanding the mechanisms of osteoclastic bone resorption is critical for the effective treatment of bone diseases in the jaw. In this review, we discuss basic principles of alveolar bone remodeling with a specific focus on the osteoclastic bone resorptive process and its unique functions in the alveolar bone. Lastly, we provide perspectives on osteoclast-targeted therapies and regenerative approaches associated with bone diseases in the jaw.

Piezo1-mediated fluid shear stress promotes OPG and inhibits RANKL via NOTCH3 in MLO-Y4 osteocytes

ABSTRACT Piezo1, a mechanosensitive ion channel, participates in a variety of biological processes in maintaining bone homeostasis. As the most abundant cells in bones of the mammals, osteocytes play an essential role in bone formation, remodeling, and bone mass maintenance. Here, by exposing MLO-Y4 osteocytes to the fluid shear stress (FSS) microenvironment, we explored the effect of Piezo1-mediated FSS on the expression of the molecules critical to the process of bone formation and resorption, Receptor Activator of Nuclear Factor-Kappa-B Ligand (RANKL) and Osteoprotegerin (OPG). It was found that 9 dyne/cm2 loading for 30 minutes showed an upregulation trend on Piezo1 when MLO-Y4 osteocytes were exposed to an FSS microenvironment. FSS promotes the expression of OPG and inhibits the expression of RANKL. The blocker of Piezo1, GsMTx4, downregulates the effect of FSS on the expression of these two molecules. In addition, NOTCH3 was involved in this process. Thus, the results demonstrated that Piezo1-mediated FSS promotes the expression of OPG and inhibits the expression of RANKL via NOTCH3 in MLO-Y4 osteocytes.

Role of the insulin-like growth factor system in bone health and military relevance during military training

Introduction: Bone is in a constant state of remodelling to remove old or damaged bone and form new bone. This process of bone resorption and formation is ‘coupled’ to preserve bone size, structure, and mass. Several physiological challenges—typical of military training and employment—can disturb bone metabolism including high levels of physical activity and energy and sleep restriction. Accumulation of damaged bone during exercise stimulates targeted remodelling, a process where the resorption of damaged bone can cause pores in the cortical bone and eventually stress fracture.

The Effect of Low-Temperature Thermal Processing on Bovine Hydroxyapatite Bone Substitutes, toward Bone Cell Interaction and Differentiation.

Ideal bone grafting scaffolds are osteoinductive, osteoconductive, and encourage osteogenesis through the remodeling processes of bone resorption, new bone formation, and successful integration or replacement; however, achieving this trifecta remains challenging. Production methods of bone grafts, such as thermal processing, can have significant effects on the degree of cell-surface interactions via wide-scale changes in the material properties. Here, we investigated the effects of small incremental changes at low thermal processing temperatures on the degree of osteoclast and osteoblast attachment, proliferation, and differentiation. Bovine bone scaffolds were prepared at 100, 130, 160, 190, and 220 °C and compared with a commercial control, Bio-Oss®. Osteoclast attachment and activity were significantly higher on lower temperature processed bone and were not present ≥190 °C. The highest osteoblast proliferation and differentiation were obtained from treatments at 130 and 160 °C. Similarly, qRT2-PCR assays highlighted osteoblasts attached to bone processed at 130 and 160 °C as demonstrating the highest osteogenic gene expression. This study demonstrated the significant effects of small-scale processing changes on bone graft materials in vitro, which may translate to a tailored approach of cellular response in vivo.

\u03b1-Mangostin inhibits LPS-induced bone resorption by restricting osteoclastogenesis via NF-\u03baB and MAPK signaling

BackgroundExcessive osteoclast activation is an important cause of imbalanced bone remodeling that leads to pathological bone destruction. This is a clear feature of many osteolytic diseases such as rheumatoid arthritis, osteoporosis, and osteolysis around prostheses. Because many natural compounds have therapeutic potential for treating these diseases by suppressing osteoclast formation and function, we hypothesized that α-mangostin, a natural compound isolated from mangosteen, might be a promising treatment as it exhibits anti‐inflammatory, anticancer, and cardioprotective effects.MethodsWe evaluated the therapeutic effect of α-mangostin on the processes of osteoclast formation and bone resorption. The receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) induces osteoclast formation in vitro, and potential pathways of α-mangostin to inhibit osteoclast differentiation and function were explored. A mouse model of lipopolysaccharide‐induced calvarial osteolysis was established. Subsequently, micro-computed tomography and histological assays were used to evaluate the effect of α-mangostin in preventing inflammatory osteolysis.ResultsWe found that α-mangostin could inhibit RANKL-induced osteoclastogenesis and reduced osteoclast‐related gene expression in vitro. F-actin ring immunofluorescence and resorption pit assays indicated that α-mangostin also inhibited osteoclast functions. It achieved these effects by disrupting the activation of NF-κB/mitogen-activated protein kinase signaling pathways. Our in vivo data revealed that α-mangostin could protect mouse calvarial bone from osteolysis.ConclusionsOur findings demonstrate that α-mangostin can inhibit osteoclastogenesis both in vitro and in vivo and may be a potential option for treating osteoclast-related diseases.

Effects of local vs systemic administration of CXCR4 inhibitor AMD3100 on orthodontic tooth movement in rats

Chemokines play pivotal roles in orthodontic tooth movement (OTM) through osteoclast-mediated bone resorption, but the underlying mechanism remains unclear. We aimed to elucidate the effects of serial local vs systemic administration of the chemokine receptor CXCR4 antagonist AMD3100 on OTM. The maxillary first molar (M1) of rats was moved mesially using a 10 g of force nickel-titanium coil spring. The injections were performed every other day with phosphate-buffered saline as a control, whereas local and systemic animals were injected with AMD3100 at the buccal palatal mucosa adjacent to M1 and subcutaneously, respectively. OTM distance and alveolar bone were examined by microcomputed tomography and histologic analysis. Osteoclast numbers were quantified using TRAP staining. Cathepsin K and stromal cell-derived factor-1 (SDF-1) were evaluated using immunohistochemistry. Reverse transcriptase polymerase chain reaction for cathepsin K, Runx2, SDF-1, CXCR4, RANKL, and OPG were also examined. OTM and osteoclast numbers were significantly decreased in the local and systemic groups compared with the control group, whereas there was no significant difference among the experimental groups. Local administration inhibited molar but not incisor movement. Trabecular thickness and trabecular spacing of the alveolar bone significantly increased, and trabecular number significantly decreased in the systemic group compared with the control group, whereas local injection also affected bone quality in the same tendency as a systemic injection. AMD3100 significantly downregulated the mRNA expression levels of cathepsin K, Runx2, SDF-1, RANKL, and RANKL/OPG ratio in both experimental groups. Local administration of AMD3100 can control initial OTM and diminish bone resorption processes during OTM via inhibition of the SDF-1/CXCR4 axis, similar to the systemic administration.

Between-Subject and Within-Subject Variaton of Muscle Atrophy and Bone Loss in Response to Experimental Bed Rest.

To improve quantification of individual responses to bed rest interventions, we analyzed peripheral quantitative computer tomography (pQCT) datasets of the lower leg of 76 participants, who took part in eight different bed rest studies. A newly developed statistical approach differentiated measurement uncertainty UMeas from between-subject-variation (BSV) and within-subject variation (WSV). The results showed that UMeas decreased 59.3% to 80% over the two decades of bed rest studies (p < 0.01), and that it was higher for muscles than for bones. The reduction of UMeas could be explained by improved measurement procedures as well as a higher standardization. The vast majority (82.6%) of the individual responses pci exceeded the 95% confidence interval defined by UMeas, indicating significant and substantial BSV, which was greater for bones than for muscles, especially at the epiphyseal measurement sites. Non-significant to small positive inter-site correlations between bone sites, but very large positive inter-site correlation between muscle sites suggests that substantial WSV exists in the tibia bone, but much less so in the calf musculature. Furthermore, endocortical circumference, an indicator of the individual’s bone geometry could partly explain WSV and BSV. These results demonstrate the existence of substantial BSV bone, and that it is partly driven by WSV, and likely also by physical activity and dietary habits prior to bed rest. In addition, genetic and epigenetic variation could potentially explain BSV, but not WSV. As to the latter, differences of bone characteristics and the bone resorption process could offer an explanation for its existence. The study has also demonstrated the importance of duplicate baseline measurements. Finally, we provide here a rationale for worst case scenarios with partly effective countermeasures in long-term space missions.