Osteoclast Function Research Articles

NVP-BHG712 alleviates ovariectomy-induced osteoporosis by modulating osteoclastogenesis

Postmenopausal osteoporosis (PMOP) is closely related to the pathogenesis of osteoclasts, with the Cathepsin K (CTSK) protein playing a crucial role. Our study aimed to screen small molecule compounds targeting CTSK and evaluate their impact on PMOP. Through molecular docking, we identified NVP-BHG712 as significantly inhibiting osteoclast differentiation and bone resorption. NVP-BHG712 also effectively suppressed CTSK activity and exhibited strong binding affinity to CTSK protein. Furthermore, NVP-BHG712 regulated the expression of inflammatory factors and modulated the balance between M1 and M2 macrophage polarization. In the mouse model of ovariectomy-induced osteoporosis, NVP-BHG712 rescued bone loss by inhibiting excessive osteoclast activation. These findings suggest that NVP-BHG712 may be a promising treatment for pathological osteoporosis by alleviating osteoclast function.

Correction of osteopetrosis in the neonate oc/oc murine model after lentiviral vector gene therapy and non-genotoxic conditioning.

Autosomal recessive osteopetrosis (ARO) is a rare genetic disease, characterized by increased bone density due to defective osteoclast function. Most of the cases are due to TCIRG1 gene mutation, leading to severe bone phenotype and death in the first years of life. The standard therapy is the hematopoietic stem cell transplantation (HSCT), but its success is limited by several constraints. Conversely, gene therapy (GT) could minimize the immune-mediated complications of allogeneic HSCT and offer a prompt treatment to these patients. The Tcirg1-defective oc/oc mouse model displays a short lifespan and high bone density, closely mirroring the human condition. In this work, we exploited the oc/oc neonate mice to optimize the critical steps for a successful therapy. First, we showed that lentiviral vector GT can revert the osteopetrotic bone phenotype, allowing long-term survival and reducing extramedullary haematopoiesis. Then, we demonstrated that plerixafor-induced mobilization can further increase the high number of HSPCs circulating in peripheral blood, facilitating the collection of adequate numbers of cells for therapeutic purposes. Finally, pre-transplant non-genotoxic conditioning allowed the stable engraftment of HSPCs, albeit at lower level than conventional total body irradiation, and led to long-term survival and correction of bone phenotype, in the absence of acute toxicity. These results will pave the way to the implementation of an effective GT protocol, reducing the transplant-related complication risks in the very young and severely affected ARO patients.

Moesin controls cell-cell fusion and osteoclast function.

Cell-cell fusion is an evolutionarily conserved process that is essential for many functions, including fertilisation and the formation of placenta, muscle and osteoclasts, multinucleated cells that are unique in their ability to resorb bone. The mechanisms of osteoclast multinucleation involve dynamic interactions between the actin cytoskeleton and the plasma membrane that are still poorly characterized. Here, we found that moesin, a cytoskeletal linker protein member of the Ezrin/Radixin/Moesin (ERM) protein family, is activated during osteoclast maturation and plays an instrumental role in both osteoclast fusion and function. In mouse and human osteoclast precursors, moesin inhibition favors their ability to fuse into multinucleated osteoclasts. Accordingly, we demonstrated that moesin depletion decreases membrane-to-cortex attachment and enhances the formation of tunneling nanotubes (TNTs), F-actin-based intercellular bridges that we reveal here to trigger cell-cell fusion. Moesin also controls HIV-1- and inflammation-induced cell fusion. In addition, moesin regulates the formation of the sealing zone, the adhesive structure determining osteoclast bone resorption area, and thus controls bone degradation, via a β3-integrin/RhoA/SLK pathway. Supporting our results, moesin - deficient mice present a reduced density of trabecular bones and increased osteoclast abundance and activity. These findings provide a better understanding of the regulation of cell-cell fusion and osteoclast biology, opening new opportunities to specifically target osteoclast activity in bone disease therapy.

LMK-235 suppresses osteoclastogenesis and promotes osteoblastogenesis by inhibiting HDAC4

Osteoblasts and osteoclasts play an important role in maintaining the structural integrity of bone tissue, in which osteoclasts degrade bone structure and osteoblasts restore bone tissue. The imbalance of osteoblast and osteoclast function can lead to many bone-related diseases, such as osteoporosis and inflammatory osteolysis. The drug that can both promote bone formation and inhibit bone loss will be able to treat those diseases. In this study, it was found that LMK-235, an selective HDAC4/5 inhibitor, inhibited the differentiation and maturation of osteoclasts by regulating NF-κB and p-Smad2/3 signaling pathways via inhibition of HDAC4. At the same time, we found that LMK-235 promoted osteoblast mineralization by upregulating Runx2 expression via inhibition of HDAC4. In vivo, LMK-235 was able to alleviate lipopolysaccharide (LPS)-induced calvarial osteolysis and promote the repair of bone defects. Taken together, LMK-235 suppresses osteoclast differentiation and promotes osteoblast formation by inhibiting HDAC4. This may provide a valuable treatment for bone diseases caused by abnormal osteoclast bone resorption and osteoblast bone regeneration.

Caffeic acid derivative MPMCA suppresses osteoclastogenesis and facilitates osteoclast apoptosis: implications for the treatment of bone loss disorders.

Osteoclast activity plays a crucial role in the pathological mechanisms of osteoporosis and bone remodeling. The treatment of these disorders involves the use of pharmacological medicines that work by inhibiting the activity of osteoclasts. Nevertheless, the prevalent and infrequent negative consequences of current antiresorptive and bone anabolic treatments pose significant drawbacks, hence restricting their prolonged administration in patients, particularly those who are elderly and/or suffer from many medical conditions. We are currently in the process of creating a new molecule called N-(4-methoxyphen) methyl caffeamide (MPMCA), which is a derivative of caffeic acid. This compound has shown potential in preventing the production of osteoclasts and causing existing osteoclasts to undergo cell apoptosis. Our investigation discovered that MPMCA hinders osteoclast function via suppressing the MAPK pathways. The expectation is that the findings of this study will stimulate the advancement of a novel approach to treating anti-resorption.

Mitochondrial protein deacetylation by SIRT3 in osteoclasts promotes bone resorption with aging in female mice

ObjectivesThe mitochondrial deacetylase sirtuin-3 (SIRT3) is necessary for the increased bone resorption and enhanced function of mitochondria in osteoclasts that occur with advancing age; how SIRT3 drives bone resorption remains elusive. MethodsTo determine the role of SIRT3 in osteoclast mitochondria, we used mice with conditional loss of Sirt3 in osteoclast lineage and mice with germline deletion of either Sirt3 or its known target Pink1. ResultsSIRT3 stimulates mitochondrial quality in osteoclasts in a PINK1-independent manner, promoting mitochondrial activity and osteoclast maturation and function, thereby contributing to bone loss in female but not male mice. Quantitative analyses of global proteomes and acetylomes revealed that deletion of Sirt3 dramatically increased acetylation of osteoclast mitochondrial proteins, particularly ATPase inhibitory factor 1 (ATPIF1), an essential protein for mitophagy. Inhibition of mitophagy via mdivi-1 recapitulated the effect of deletion of Sirt3 or Atpif1 in osteoclast formation and mitochondrial function. ConclusionsDecreasing mitophagic flux in osteoclasts may be a promising pharmacotherapeutic approach to treat osteoporosis in older adults.

Oxysophocarpine attenuates inflammatory osteolysis by modulating the NF-κb pathway and the reactive oxygen species-related Nrf2 signaling pathway.

Inflammatory diseases often result in bone loss due to persistent inflammation, which activates osteoclasts and increases bone resorption. Oxysophocarpine (OSC), a bioalkaloid extracted from the roots of Sophora japonica and other leguminous plants, has neuroprotective and anti-tumor properties. However, it is still uncertain whether OSC can effectively inhibit the differentiation of osteoclasts and bone resorption. Therefore, this study explored the potential role of OSC in osteoclast formation and inflammatory osteolysis and its underlying mechanisms. This study involved inducing primary mouse bone marrow macrophages (BMMs) into osteoclasts using macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL) and examined the effects of OSC on osteoclast (OC) differentiation, function, and intracellular reactive oxygen species (ROS) production. The impact of OSC on the expression of osteoclast-specific genes and inflammation-related factors was assessed using real-time quantitative PCR. Additionally, changes in oxidative stress-related factors, NF-κB, and MAPK signaling pathways were examined using western blotting. Finally, this study investigated the influence of OSC on a mouse cranial bone resorption model induced by titanium (Ti) particles in vivo. OSC inhibited OC differentiation and resorption and reduces intracellular ROS levels. Moreover, OSC suppressed IL-1β, TNF-α, IL-6, and osteoclast-specific gene transcription while increasing Nrf2 and HO-1 protein expression. Furthermore, OSC inhibited the expression and autoregulation of the NFATc1 gene, ultimately leading to a reduction in Ti particle-induced bone resorption in mice. OSC could be regarded as an innovative medication for the treatment of osteoclast-associated inflammatory osteolytic diseases.

S100P binds to RAGE and activates ERK/NF-κB signaling to promote osteoclast differentiation and activity

S100 calcium-binding protein P (S100P) is a secretory protein that is expressed in various healthy tissues and tumors. Megakaryocyte-secreted S100P promotes osteoclast differentiation and function; however, its receptor and cellular signaling in osteoclasts remain unclear. Receptor for advanced glycation end products (RAGE), which is the receptor for S100P on cancer cells, was expressed in osteoclast precursors, and S100P-RAGE binding was confirmed through co-immunoprecipitation. Additionally, the phosphorylation of ERK and NF-κB was increased in S100P-stimulated osteoclast precursors but was inhibited by addition of the RAGE antagonistic peptide (RAP). S100P-induced osteoclast differentiation and excessive bone resorption activity were also reduced by the addition of RAP. This study demonstrates that S100P, upon binding with RAGE, activates the ERK and NF-κB signaling pathways in osteoclasts, leading to increased cell differentiation and bone resorption activity.

The Manganese-Bone Connection: Investigating the Role of Manganese in Bone Health.

The complex relationship between trace elements and skeletal health has received increasing attention in the scientific community. Among these minerals, manganese (Mn) has emerged as a key element affecting bone metabolism and integrity. This review examines the multifaceted role of Mn in bone health, including its effects on bone regeneration, mineralization, and overall skeletal strength. This review article is based on a synthesis of experimental models, epidemiologic studies, and clinical trials of the mechanisms of the effect of Mn on bone metabolism. Current research data show that Mn is actively involved in the processes of bone remodeling by modulating the activity of osteoblasts and osteoclasts, as well as the main cells that regulate bone formation and resorption. Mn ions have a profound effect on bone mineralization and density by intricately regulating signaling pathways and enzymatic reactions in these cells. Additionally, Mn superoxide dismutase (MnSOD), located in bone mitochondria, plays a crucial role in osteoclast differentiation and function, protecting osteoclasts from oxidative damage. Understanding the nuances of Mn's interaction with bone is essential for optimizing bone strategies, potentially preventing and managing skeletal diseases. Key findings include the stimulation of osteoblast proliferation and differentiation, the inhibition of osteoclastogenesis, and the preservation of bone mass through the RANK/RANKL/OPG pathway. These results underscore the importance of Mn in maintaining bone health and highlight the need for further research into its therapeutic potential.

Targeting BRD4 to attenuate RANKL-induced osteoclast activation and bone erosion in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that can cause destruction of cartilage and bone's extracellular matrix. Bromodomain 4 (BRD4), as a transcriptional and epigenetic regulator, plays a key role in cancer and inflammatory diseases. While, the role of BRD4 in bone destruction in RA has not been extensively reported. Our study aimed to investigate the effect of BRD4 on the bone destruction in RA and, further, its mechanism in the pathogenesis of the disease. In this study, receiving approval from the Ethical Committee of the Affiliated Hospital of Qingdao University, we evaluated synovial tissues from patients with RA and OA for BRD4 expression through advanced techniques such as immunohistochemistry, quantitative real-time PCR (qRT-PCR), and Western blotting. We employed a collagen-induced arthritis (CIA) mouse model to assess the therapeutic efficacy of the BRD4 inhibitor JQ1 on disease progression and bone destruction, supported by detailed clinical scoring and histological examinations. Further, in vitro osteoclastogenesis assays using RAW264.7 macrophages, facilitated by TRAP staining and resorption pit assays, provided insights into the mechanistic effects of JQ1 on osteoclast function. Statistical analysis was rigorously conducted using SPSS, applying Kruskal-Wallis, one-way ANOVA, and Student's t-tests to validate the data. In our study, we found that BRD4 expression significantly increased in the synovial tissues of RA patients and the ankle joints of CIA mice, with JQ1, a BRD4 inhibitor, effectively reducing inflammation, arthritis severity (p < 0.05), and bone erosion. Treatment with JQ1 not only improved bone mass and structural integrity in CIA mice but also downregulated osteoclast-related gene expression and the RANKL/RANK signaling pathway, indicating a suppression of osteolysis. Furthermore, in vitro assays demonstrated that JQ1 markedly inhibited osteoclast differentiation and function, underscoring the pivotal role of BRD4 in osteoclastogenesis and its potential as a target for therapeutic intervention in RA-induced bone destruction. Our study concludes that targeting BRD4 with the inhibitor JQ1 significantly mitigates inflammation and bone destruction in rheumatoid arthritis, suggesting that inhibition of BRD4 may be a potential therapeutic strategy for the treatment of bone destruction in RA.

The role of calcium channels in osteoporosis and their therapeutic potential.

Osteoporosis, a systemic skeletal disorder marked by diminished bone mass and compromised bone microarchitecture, is becoming increasingly prevalent due to an aging population. The underlying pathophysiology of osteoporosis is attributed to an imbalance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. Osteoclasts play a crucial role in the development of osteoporosis through various molecular pathways, including the RANK/RANKL/OPG signaling axis, cytokines, and integrins. Notably, the calcium signaling pathway is pivotal in regulating osteoclast activation and function, influencing bone resorption activity. Disruption in calcium signaling can lead to increased osteoclast-mediated bone resorption, contributing to the progression of osteoporosis. Emerging research indicates that calcium-permeable channels on the cellular membrane play a critical role in bone metabolism by modulating these intracellular calcium pathways. Here, we provide an overview of current literature on the regulation of plasma membrane calcium channels in relation to bone metabolism with particular emphasis on their dysregulation during the progression of osteoporosis. Targeting these calcium channels may represent a potential therapeutic strategy for treating osteoporosis.

Lysosomal biogenesis and function in osteoclasts: a comprehensive review.

Lysosomes serve as catabolic centers and signaling hubs in cells, regulating a multitude of cellular processes such as intracellular environment homeostasis, macromolecule degradation, intracellular vesicle trafficking and autophagy. Alterations in lysosomal level and function are crucial for cellular adaptation to external stimuli, with lysosome dysfunction being implicated in the pathogenesis of numerous diseases. Osteoclasts (OCs), as multinucleated cells responsible for bone resorption and maintaining bone homeostasis, have a complex relationship with lysosomes that is not fully understood. Dysregulated function of OCs can disrupt bone homeostasis leading to the development of various bone disorders. The regulation of OC differentiation and bone resorption for the treatment of bone disease have received considerable attention in recent years, yet the role and regulation of lysosomes in OCs, as well as the potential therapeutic implications of intervening in lysosomal biologic behavior for the treatment of bone diseases, remain relatively understudied. This review aims to elucidate the mechanisms involved in lysosomal biogenesis and to discuss the functions of lysosomes in OCs, specifically in relation to differentiation, bone resorption, and autophagy. Finally, we explore the potential therapeutic implication of targeting lysosomes in the treatment of bone metabolic disorders.

Nanographene Oxide Promotes Angiogenesis by Regulating Osteoclast Differentiation and Platelet-Derived Growth Factor Secretion.

An imbalanced system of angiogenesis-osteoblasts-osteoclasts is regarded as the main factor in bone remodeling dysfunction diseases or osseointegration loss. Osteoclast precursors are the key cells that accelerate bone-specific angiogenesis and maintain normal osteoblast and osteoclast function. Graphene oxide is an effective scaffold surface modification agent with broad application prospects in bone tissue engineering. However, the effect of graphene oxide on the interaction between osteoclasts and angiogenesis has not yet been elucidated. In this study, a rat calvarial defect model was established and treated with an electrochemically derived nanographene oxide (ENGO) hydrogel. Higher angiogenesis and platelet-derived growth factor (PDGF) B in preosteoclasts were observed in the ENGO group compared with that in the control group. Moreover, in vitro experiments demonstrate the efficacy of ENGO in substantially reducing the expression of the receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclast-associated markers and inhibiting bone resorption activity. Additionally, ENGO enhances the secretion of the osteoclast-derived coupling factor PDGF-BB and promotes angiogenesis. Our investigation revealed the crucial role of isocitrate dehydrogenase 1 (IDH1) in the ENGO-mediated regulation of osteoclast differentiation and PDGF-BB secretion. The decreased expression of IDH1 reduces the level of histone lysine demethylase 7A (KDM7A) and subsequently increases the H3K9me2 level in the cathepsin K promoter region. In summary, we found that ENGO promotes angiogenesis by inhibiting the maturity of RANKL-induced osteoclasts and enhancing PDGF-BB secretion. These results indicate that ENGO holds promise for the application in fostering osteoclast-endothelial cell crosstalk, providing an effective strategy for treating bone resorption and osteoclast-related bone loss diseases.

5-Lipoxygenase: The Therapeutically Unexplored Target for Bone Health

Bone fracture is a common orthopedic condition that represents a significant health concern. Bone fracture repair process is a complex process that involves the harmonic and synchronized activity of bone cells. 5-lipoxygenase (5-LOX) is an enzyme responsible for the conversion of arachidonic acid to form leukotrienes. While leukotrienes have an empirical inflammatory role, various evidence suggests that these 5-LOX mediators, by switching the inflammatory environment and altering the activity of bone cells, have a detrimental effect on the bone fracture healing process. Additionally, various evidence suggests that 5-LOX inhibition shows improvement in the overall bone healing process and improves overall bone health. Despite this evidence, the clinical use of 5-LOX inhibitors in bone fracture healing is largely unexplored. The current review aimed to summarize the available evidences and pave the way for future large scale pre-clinical and clinical studies to evaluate the effectiveness of selective 5-LOX inhibitors in bone fracture healing. A comprehensive literature search was conducted in PubMed, Google Scholar, and ScienceDirect to identify relevant articles related to the effect of 5-LOX in bone health. The summary of available scientific evidence highlights that the selective 5-LOX inhibition can modulate the functioning of osteoclasts and osteoblasts, favoring faster bone fracture healing. The observations of this study support the selective 5-LOX inhibition as a potential treatment option that can improve bone fracture healing rate and therefore future clinical studies can be designed to confirm the observations of the current review study.

Aromatase inhibitor-induced bone loss osteosarcopenia in older patients with breast cancer: effects of the RANK/RANKL system's inhibitor denosumab vs. bisphosphonates.

The raising number of older patients who are diagnosed with breast cancer represents a significant medical and societal challenge. Aromatase inhibitors (AI), which are commonly utilized to treat this condition in these patients have significant adverse events on bone and muscle health. Falling estrogen production leads to an increase in RANKL secretion by osteoblasts with accelerated bone remodeling due to osteoclast activity. Furthermore, estrogen deficiency reduces skeletal muscle strength and mass. The humanized monoclonal antibody, denosumab, neutralizes RANKL, thereby inhibiting osteoclast formation, function and survival and ultimately exerting powerful anti-resorptive effects.. In this study, we report on the efficacy of denosumab in mitigating aromatase inhibitor-induced bone loss (AIBL) and sarcopenia in older women with breast cancer. From January 2022 to January 2023, we enrolled 30 patients (female sex, ≥ 65years) diagnosed with non-metastatic breast cancer undergoing adjuvant endocrine therapy; patients received, as per clinical practice, primary bone prophylaxis with denosumab (60mg via subcutaneous injection every 6months) according to oncologic guidelines. This group was matched with 30 patients with non-metastatic breast cancer, who were treated with biphosphonates (BF) therapy (oral alendronate 70mg/week). For each patient bone mineral density (BMD) and bone quality in terms of trabecular bone score (TBS) in addition to body composition and Relative Skeletal Muscle Index (RSMI) was assessed by bone densitometry at baseline and after one year of treatment. Significant improvements in TBS at the lumbar spine, RSMI and whole-body composition (arms, legs, and trunk) were observed in the denosumab group compared with the BF group. These findings underscore the role of denosumab as an effective strategy in managing AIBL and osteosarcopenia in older women with breast cancer and undergoing adjuvant endocrine therapy, which is crucial for improving quality of life, preventing functional decline, and optimizing treatment outcomes.

Significance of zoledronic acid in the adjuvant therapy in patients with breast cancer

Introduction. Zoledronic acid is a medicine belonging to the bisphosphonate group. Its action is to inhibit the function of osteoclasts, which leads to a reduction in bone resorption. This preparation has a proven effect in the treatment of osteoporosis and Paget’s disease. Bisphosphonates have also found use in the treatment of breast cancer. Studies conducted for many years indicate that zoledronic acid works most favorably in combination with adjuvant therapy. Breast cancer patients who are postmenopausal and being treated with chemotherapy are at risk of bone mass loss and hypercalcemia. Bisphosphonates effectively manage this. In addition, zoledronic acid indirectly exerts anticancer effects by modulating the immune system. All this allows us to conclude that taking this drug reduces the risk of bone metastasis in breast cancer patients. Dosage is also key in all this. There are several regimens offered to osteoporosis and breast cancer patients. So far, the following have been studied: conventional dosing (4 mg IV every 3-4 weeks), maintenance dosing (4 mg IV every 3-6 months) and metronomic dosing (1 mg IV weekly). It cannot be ruled out that each of these regimens may have a different antitumor effect. By reviewing scientific works, we aim to present the treatment options with zoledronic acid for breast cancer patients. We will describe the impact on their results depending on the dosage and we will present the other side of the coin, which are the side effects of taking this preparation. Aim. This review provides an overview of the effects and impact of zoledronic acid in adjuvant therapy in patients with breast cancer. Material and methods. The article presents the current state of knowledge on zoledronic acid as an adjuvant treatment option in breast cancer patients. It is a detailed literature review using Google Scholar, PubMed and Journal of Education Health and Sport platforms. Publications using the following key words were analyzed: bisphosphonates, zoledronic acid, osteoporosis, breast cancer, bone metastases. Conclusion. Women diagnosed with breast cancer should be treated in a multidisciplinary manner. We treat early detected cancers to achieve complete remission. Long-term survival is our primary goal, and in pursuing it we should consider the potential impact of this treatment on the patient’s skeletal system. Clinical studies allow us to conclude that there is a correlation between the initiation of antiresorptive therapy at an early stage of cancer and overall survival. Additionally, zoledronic acid significantly reduced the number of fractures. The collected data allow us to conclude that the addition of zoledronic acid to the established treatment regimens has a potentially positive effect on the group of postmenopausal patients undergoing tamoxifen treatment or with existing bone metastases. Keywords: bisphosphonates, zoledronic acid, breast cancer, osteoporosis, bone metastases.

Osteogenic effect of an adiponectin-derived short peptide that rebalances bone remodeling: a potential disease-modifying approach for postmenopausal osteoporosis therapy.

Adiponectin, an adipokine, regulates metabolic processes, including glucose flux, lipid breakdown, and insulin response, by activating adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2). We have previously shown that globular adiponectin (gAd), an endogenous form of adiponectin, has osteoanabolic and anti-catabolic effects in rodent models of postmenopausal osteopenia. Moreover, we reported the identification of a 13-mer peptide (ADP-1) from the collagen domain of adiponectin, which exhibited significant adiponectin-mimetic properties. Since the clinical development of gAd is constrained by its large size, here, we investigated the osteogenic property of ADP-1. ADP-1 induced osteoblast differentiation more potently than gAd. ADP-1 elicited osteoblast differentiation through two downstream pathways that involved the participation of adiponectin receptors. Firstly, it enhanced mitochondrial biogenesis and OxPhos, leading to osteoblast differentiation. Secondly, it activated the Akt-glycogen synthase kinase 3β-Wnt pathway, thereby increasing osteoblast differentiation. Additionally, ADP-1 suppressed the production of receptor-activator of nuclear kappa B ligand from osteoblasts, enabling it to act as a dual-action molecule (suppressing osteoclast function besides promoting osteoblast function). In osteopenic ovariectomized rats, ADP-1 increased bone mass and strength and improved trabecular integrity by stimulating bone formation and inhibiting bone resorption. Furthermore, by increasing ATP-producing intermediates within the tricarboxylic acid cycle in bones, ADP-1 likely fueled osteoblast function. Given its dual-action mechanism and high potency, ADP-1 offers a unique opportunity to address the unmet clinical need to reset the aberrant bone remodeling in osteoporosis to normalcy, potentially offering a disease-modifying impact.

Root resorption of primary molars and dental development of premolars in children with Osteogenesis Imperfecta medicated with bisphosphonates, grouped according to age and gender

BackgroundOsteogenesis imperfecta (OI) is an inherited disorder characterized by bone fragility and skeletal alterations. The administration of bisphosphonates (BPs) to patients with OI reduces pain, thereby improving their quality of life. The main mechanism of action of BPs is the inhibition of osteoclast action. In the oral cavity of children with OI during growth and development, physiological processes that require the function of osteoclasts occur. The aim of this investigation was to study the dental development of premolars and the root resorption of primary molars in children with OI medicated with BPs according to age and sex.MethodsAn observational and analytical study was designed. The study sample consisted of 26 6- to 12-year-old children with a confirmed diagnosis of OI treated with BPs with available panoramic radiographs. The control group consisted of 395 children with available panoramic radiographs. Both groups were divided into subgroups according to sex and age. The third quadrant was studied, focusing on the first left temporary molar (7.4), the second left temporary molar (7.5), the first left permanent premolar (3.4) and the second left permanent premolar (3.5). The Demirjian method was used to study the dental development of 3.4 and 3.5, and the Haavikko method was used to study the root resorption of 7.4 and 7.5. The Mann‒Whitney U test was used for comparisons, and p < 0.05 indicated statistical significance.ResultsThe mean chronological age of the 421 patients was 9.21 years (95% CI 9.05–9.37). The sample was reasonably balanced by sex, with 52.5% (221 patients) boys versus 47.5% (200 patients) girls. Delayed exfoliation and tooth development were described in children with OI (p = 0.05). According to sex, the root resorption of primary molars and tooth development were significantly lower in boys in both groups and in girls in the OI group, but the differences between the age groups were not significant.ConclusionsChildren with OI treated with BPs exhibit delayed dental development of the premolars and delayed root resorption of the primary molars. Boys exhibited delays in both variables, but the differences by age subgroup were not significant. These clinical findings support the importance of clinically and radiographically monitoring the dental development and root resorption of primary teeth in children with OI treated with BPs to avoid alterations of the eruptive process.

Suppressing ERp57 diminishes osteoclast activity and ameliorates ovariectomy-induced bone loss via the intervention in calcium oscillation and the calmodulin/calcineurin/Nfatc1 pathway

BackgroundIncreased osteoclast activity constitutes the primary etiology of excessive bone erosion in postmenopausal osteoporosis. ERp57, otherwise referred to as protein disulfide isomerase A3 (PDIA3), plays a crucial role in the regulation of intracellular calcium signaling. This is documented to exert a profound impact on osteoclast differentiation and functionality. MethodsTo ascertain the potential role of ERp57 in disease progression, prevention, and treatment, network pharmacology and bioinformatics analyses were conducted in relation to postmenopausal osteoporosis and ERp57 inhibitor (Loc14). Then, subsequent experimental verifications were employed in vitro on osteoclast and osteoblast, and in vivo on ovariectomy (OVX) mice models. ResultsMultiple enrichment analyses suggested that the “calcium signaling pathway” may constitute a potential avenue for therapeutic intervention by Loc14 in the treatment of postmenopausal osteoporosis. In vitro experiments demonstrated inhibition of ERp57 could block osteoclast differentiation and function by interfering with the expression of osteoclast marker genes (Traf6, Nfatc1, and Ctsk). Further mechanisms studies based on calcium imaging, qPCR, and WB established that ERp57 inhibitor (Loc14) could obstruct calcium oscillation in osteoclast precursor cells (OPCs) by limiting the entry sources of cytosolic Ca2+ and interfering with calmodulin/calcineurin/Nfatc1 pathway. Evidence from Micro-CT scanning and double calcein labeling confirmed that the application of Loc14 in vivo could alleviate bone loss and partially reversed the osteogenic impairment caused by OVX in mice. ConclusionsOur findings proved the suppressive effects of Loc14 on osteoclastogenesis via attenuating calcium oscillation and associated singling pathways, providing ERp57 as a potential therapeutic target for postmenopausal osteoporosis.

Impact of the SIK3 pathway inhibition on osteoclast differentiation via oxidative phosphorylation.

Maintenance of bone homeostasis and the balance between bone resorption and formation are crucial for maintaining skeletal integrity. This study sought to investigate the role of salt-inducible kinase 3 (SIK3), a key regulator in cellular energy metabolism, during the differentiation of osteoclasts. Despite osteoclasts being high energy-consuming cells essential for breaking down mineralized bone tissue, the specific function of SIK3 in this process remains unclear. To address this issue, we generated osteoclast-specific SIK3 conditional knockout mice and assessed the impact of SIK3 deletion on bone homeostasis. Our findings revealed that SIK3 conditional knockout mice exhibited increased bone mass and an osteopetrosis phenotype, suggesting a pivotal role for SIK3 in bone resorption. Moreover, we assessed the impact of pterosin B, a SIK3 inhibitor, on osteoclast differentiation. The treatment with pterosin B inhibited osteoclast differentiation, reduced the numbers of multinucleated osteoclasts, and suppressed resorption activity in vitro. Gene expression analysis demonstrated that SIK3 deletion and pterosin B treatment influence a common set of genes involved in osteoclast differentiation and bone resorption. Furthermore, pterosin B treatment altered intracellular metabolism, particularly affecting key metabolic pathways, such as the tricarboxylic acid cycle and oxidative phosphorylation. These results provide valuable insights into the involvement of SIK3 in osteoclast differentiation and the molecular mechanisms underlying osteoclast function and bone diseases.