Osteoclast Activity Research Articles

Developing long bones respond to surrounding tissues by trans-pairing of periosteal osteoclasts and endocortical osteoblasts.

Developing long bones alter their shape while maintaining uniform cortical thickness via coordinated activity of bone-forming osteoblasts and bone-resorbing osteoclasts at periosteal and endosteal surfaces, a process we designate trans-pairing. Two types of trans-pairing shift cortical bone in opposite orientations: peri-forming trans-pairing (peri-t-p) increases bone marrow space and endo-forming trans-pairing (endo-t-p) decreases it, via paired activity of bone resorption and formation across the cortex. Here, we focused on endo-t-p in growing bones. Analysis of endo-t-p activity in the cortex of mouse fibulae revealed osteoclasts under the periosteum compressed by muscles, and expression of RANKL in periosteal cells of the cambium layer. Furthermore, mature osteoblasts were localized on the endosteum, while preosteoblasts were at the periosteum and within cortical canals. X-ray tomographic microscopy revealed the presence of cortical canals more closely associated with endo- than with peri-t-p. Sciatic nerve transection followed by muscle atrophy and unloading induced circumferential endo-t-p with concomitant spread of cortical canals. Such canals likely supply the endosteum with preosteoblasts from the periosteum under endo-t-p, allowing bone shape to change in response to mechanical stress or nerve injury.

Guanylate cyclase promotes osseointegration by inhibiting oxidative stress and inflammation in aged rats with iron overload.

This study intended to investigate the effect of vericiguat (VIT) on titanium rod osseointegration in aged rats with iron overload, and also explore the role of VIT in osteoblast and osteoclast differentiation. In this study, 60 rats were included in a titanium rod implantation model and underwent subsequent guanylate cyclase treatment. Imaging, histology, and biomechanics were used to evaluate the osseointegration of rats in each group. First, the impact of VIT on bone integration in aged rats with iron overload was investigated. Subsequently, VIT was employed to modulate the differentiation of MC3T3-E1 cells and RAW264.7 cells under conditions of iron overload. Utilizing an OVX rat model, we observed significant alterations in bone mass and osseointegration due to VIT administration in aged rats with iron overload. The observed effects were concomitant with reductions in bone metabolism, oxidative stress, and inflammation. To elucidate whether these effects are associated with osteoclast and osteoblast activity, we conducted in vitro experiments using MC3T3-E1 cells and RAW264.7 cells. Our findings indicate that iron accumulation suppressed the activity of MC3T3-E1 while enhancing RAW264.7 function. Furthermore, iron overload significantly decreased oxidative stress levels; however, these detrimental effects can be mitigated by VIT treatment. Collectively, our data provide compelling evidence that VIT has the potential to reverse the deleterious consequences of iron overload on osseointegration and bone mass during ageing.

Prevalence of maxillary sinus pneumatization in partially or totally edentulous patients according to the Carl Misch classification, diagnosed by CBCT in a private radiology center in the city of Cuenca, 2021 - 2022

The maxillary sinus is the largest of the paranasal sinuses, located in the body of the maxillary bone. Its pneumatization process is part of its growth and development. After tooth loss, osteoclastic activity begins in Schneider's membrane, which causes the maxillary sinuses to increase in size, a situation that complicates prosthetic rehabilitation and implant placement. Objective: To determine the degree of pneumatic sinus pneumatization based on Carl Misch's classification in partial or edentulous patients treated in a private radiology center in the city of Cuenca diagnosed by CBCT in 2021-2022. Methodology: Study of observational, descriptive, and cross-sectional types. Seventy-three cone-beam tomographic studies of total and partially edentulous patients considering the area from canines to second molars were examined, based on Carl Misch's classification, to determine the degree of pneumatization and the depth of the maxillary sinus. Results: grade III pneumatization was the most prevalent in 43.41% of the total 129 maxillary sinuses evaluated, a grade IV was mostly in total edentulous (17.05%), and partial edentulous a grade III was more predominant (27.13%). Conclusion: The relationship between the degree of pneumatization and the depth of the maxillary sinus was evident, determining that there is a relationship between the loss of dental pieces and the pneumatization of the maxillary sinus, and these results can help plan surgical procedures and to take into account possible complications in patients with a higher degree of pneumatization.

B10 cells regulate macrophage polarization to alleviate inflammation and bone loss in periodontitis.

The polarization of macrophages into an anti-inflammatory phenotype is crucial for resolving periodontal inflammation. It has been reported that B10 cells can regulate the immune response of macrophages during inflammation and are also able to regulate inflammation in periodontitis. However, whether B10 cells' regulation function in periodontitis is related to macrophage polarization remains unclear. This study aims to investigate whether B10 cells can regulate macrophage polarization in periodontitis. Macrophages were cocultured with B10 cells in vitro for 5days. After coculture, macrophages were obtained for analysis directly or followed by stimulation with Pg-LPS/IFN-γ or IL-4/IL-13. Flow cytometry and/or reverse transcriptase-polymerase chain reaction (RT-PCR) were employed to detect the expression of IL-1β, iNOS, TNF-α, CD206, and ARG-1 in macrophages. B10 cells were transferred on the 5th day after ligation in wild or macrophage-depletion mice. Toluidine blue and TRAP staining were used to evaluate alveolar bone resorption and osteoclast activation. Immunohistochemistry was employed to detect the expression of CD68, IL-1β, TNF-α, iNOS, ARG-1, and IL-10. Immunofluorescence was used to detect the expression of CD68+CD86+M1 macrophages and CD68+CD206+M2 macrophages. In vitro, B10 cells inhibit the expression of IL-1β, iNOS, and TNF-α in macrophages while increasing the expression of CD206 and ARG-1. In experimental periodontitis, B10 cells inhibit the polarization of CD68+CD86+M1 macrophages and iNOS expression but enhance the polarization of CD68+CD206+M2 macrophages and ARG-1 expression. Importantly, the depletion of macrophages partially weakened the regulation function of B10 cells in periodontitis. B10 cells promote M2 macrophage polarization, inhibit M1 macrophage polarization in periodontitis, and alleviate periodontitis partially by regulating macrophage polarization.

Effects of T-2 and deoxynivalenol mycotoxins on mouse spinal bone growth and integrity

Kashin-Beck Disease (KBD), an osteoarticular disorder, is influenced by various factors, including exposure to Deoxynivalenol (DON) and T-2 mycotoxins. This study systematically explored the impact of these mycotoxins on the development and structural resilience of spinal structures in mice, examining both isolated and combined effects. The experiment involved 72 male mice divided into nine groups, each subjected to varying concentrations of T-2, DON, or their combinations over four weeks. Rigorous monitoring included body weight, key indicators of bone metabolism, and cellular activities essential to bone health. Comprehensive evaluations using biomechanical analysis, x-ray, and micro-computed tomography (micro-CT) were conducted to assess alterations in spinal structure.The findings revealed a pivotal aspect: mice exhibited a dose-dependent decline in body weight when exposed to individual mycotoxins, while simultaneous exposure produced an unanticipated antagonistic effect. Moreover, decreases were noted in levels of calcium, phosphorus, and vitamin D, coupled with changes in the activities of osteoblasts (increased) and osteoclasts (decreased), all intricately tied to the toxins' dosages and combinations. Notably, variations in the biomechanical properties corresponded with the mycotoxin dosage and blend, showing a decline in biomechanical strength. Micro-CT analyses further substantiated the profound toxic impact of the toxin dosage and mixtures on both the cortical and trabecular components of the spinal structures.In summary, this investigation unequivocally illuminates the dose- and ratio-dependent deleterious impacts of DON and T-2 mycotoxins on the growth and structural soundness of spinal structures in mice. These findings highlight the urgent need for a comprehensive understanding of the potential hazards these toxins pose to bone health, providing invaluable guidance for future toxicological research and public health strategies.

The Effect of Gold Nanoparticles and Apricot Kernel Extract on the Osseointegration of Dental Implants - A Rabbit Model

Introduction The osseointegration of dental implants is critical to their longevity and success. Various factors such as surface modifications, both additive and subtractive, systemic drug administration, growth factors, and plasma derivatives can influence osseointegration. Aims and Objectives This study aimed to study the effects of gold nanoparticles and aqueous extract of apricot kernels on the osseointegration of titanium implants in the tibia of rabbits. Materials and Methods Apricot kernels were dried, grounded, and dissolved in water to obtain an aqueous extract. It was filtered and stored in the refrigerator at 4oC. Gold nanoparticles (AuNPs) were prepared by mixing 3 ml of 0.02 mM hydrogen tetrachloroaurate with 1 ml of olive leaf extract. The mixture was stirred vigorously for 15 minutes on a heater stirrer at 50oC. Titanium screw implants were sterilized in an autoclave at 120oC with 15 pounds per square inch for 30 minutes. Sterilized implants were stored in sealed containers until use. The study was carried out at the College of Veterinary Medicine, University of Mosul, Iraq. The ethical approval for the study was obtained from the institutional animal care and use committee, College of Veterinary Medicine, University of Mosul, Mosul, Iraq, on 15/04/2023 on reference no UM.VET.2023.013. Nine healthy male adult white New Zealand rabbits aged between 10-12 months were utilized for the study. Three pure titanium implants, each of a type, were placed in each tibia. The implants were categorized as follows: control group (18 uncoated implants) and experimental group (36 coated implants). The implant placement was divided into three groups: controls with uncoated implants (n=18), AuNPs-coated implants (n=18), and apricot kernel extract-coated implants (n=18). General anesthesia was induced by intramuscular injection of ketamine hydrochloride 50mg (1ml /kg of body weight) plus xylazine 2% (0.2 ml /kg of body weight). The AuNPs-coated implants were implanted in the superior osteotomy site in the tibia. The apricot kernel extract-coated implants were implanted in the inferior osteotomy site and the uncoated implants were implanted in the middle osteotomy sites. Histological and histomorphometric tests were performed on all bone implant blocks at one-week, two-week, and three-week intervals after implant placement. The results were evaluated based on the amount of bone formation, cellular components, and inflammation. Tabulated data were statistically analyzed using SPSS v23.0 (IBM, Armonk, NY) using ANOVA with a statistical significance of p <0.05 Results We observed a significant amount of osteogenesis with reduced inflammation in AuNPs-coated implants and apricot kernel extract-coated implants compared to untreated implants. The osteoclastic activity was significantly higher in untreated implants than the treated implant sites. A statistically significant association was observed between coated implants and untreated implants. Conclusion The application of gold nanoparticles and aqueous extract of apricot kernels appears to be promising in reducing inflammation and improving bone apposition on the titanium implant surface. However, this preliminary investigation warrants further research.

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.

Irilin D suppresses RANKL-induced osteoclastogenesis and prevents inflammation-induced bone loss by disrupting the NF-κB and MAPK signaling pathways

Excessive activity of osteoclasts(OCs) lead to bone resorption in chronic inflammatory conditions. The use of natural compounds to target OCs offers significant promise in the treatment or prevention of OC-associated diseases. Irilin D (IRD), a natural isoflavone derived from Belamcanda chinensis (L.) DC., has potential effects on OC differentiation both in vitro and in vivo that have yet to be thoroughly explored. In our study, we found that IRD inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced OC differentiation, actin ring formation, and bone resorption in vitro without compromising cell viability. However, IRD did not exhibit anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated macrophages. Furthermore, IRD reduced LPS-induced inflammatory bone loss by blocking osteoclastogenesis in a mouse model. Mechanistically, IRD disrupted RANKL-induced activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB), leading to the inhibition of c-Fos and nuclear factor of activated T cells cytoplasmic 1 (NFATc1) activation. We also demonstrated that IRD inhibited RANKL-induced osteoclastic NFATc1 target genes, including DC-STAMP, ACP5, and CtsK. Our results indicate that IRD mitigates LPS-induced inflammatory bone resorption in mice by inhibiting RANKL-activated MAPKs and NF-κB signaling pathways, suggesting its potential as a natural isoflavone for preventing or treating OC-associated diseases.

Urinary PYD/Creatinine Ratio Has Negative Correlation to Serum 25(OH)D and Positive Correlation to Chronic Lead Exposure Index

BACKGROUND: The burden of disease due to lead exposure continues to increase. Lead interferes with 25(OH)D hydroxylation and calcium transport, increasing osteoclastic activity and bone resorption. Pyridinoline crosslinks (PYD), as an indicator of bone damage, can be seen earlier compared to imaging changes. Therefore, it is necessary to determine the correlation between serum 25(OH)D levels and the urinary PYD/creatinine ratio in workers exposed to lead, since up to now, there are only limited studies related to it.METHODS: This cross-sectional study involved 104 workers exposed to lead, selected from parents whose children had blood lead levels above 10 µg/dL. Questionnaires and physical examination were performed to obtain characteristic data from subjects. Data regarding blood lead levels, serum 25(OH)D levels, urinary PYD levels, and urinary creatinine levels were also obtained from various laboratory methods.RESULTS: Most subjects (86.5%) had inadequate serum 25(OH)D. Median blood lead levels was 6.3 (1.2-35.5) µg/dL, chronic lead exposure index was 35.3 (1.2-535.8) years µg/dL, serum 25(OH)D levels was 22 (8-52) ng/mL, and urinary PYD/creatinine ratio was 5.3 (3.6-28.1)×10-6. There was a significant negative correlation between serum 25(OH)D levels and urinary PYD/creatinine ratio in workers exposed to lead. There was also a significant positive correlation between chronic lead exposure index and the urinary PYD/creatinine ratio.CONCLUSION: Since urinary PYD/creatinine ratio is correlated with serum chronic lead exposure index and serum 25(OH)D levels, it suggests that pyridinoline might be a potential biomarker to detect bone metabolism disorder due to the chronic lead exposure. Vitamin D adequacy is also an important factor in preventing bone metabolism disorder amidst chronic lead exposure.KEYWORDS: 25(OH)D, bone resorption, pyridinoline, lead, worker

SREBP2 restricts osteoclast differentiation and activity by regulating IRF7 and limits inflammatory bone erosion

Osteoclasts are multinucleated bone-resorbing cells, and their formation is tightly regulated to prevent excessive bone loss. However, the mechanisms by which osteoclast formation is restricted remain incompletely determined. Here, we found that sterol regulatory element binding protein 2 (SREBP2) functions as a negative regulator of osteoclast formation and inflammatory bone loss. Cholesterols and SREBP2, a key transcription factor for cholesterol biosynthesis, increased in the late phase of osteoclastogenesis. The ablation of SREBP2 in myeloid cells resulted in increased in vivo and in vitro osteoclastogenesis, leading to low bone mass. Moreover, deletion of SREBP2 accelerated inflammatory bone destruction in murine inflammatory osteolysis and arthritis models. SREBP2-mediated regulation of osteoclastogenesis is independent of its canonical function in cholesterol biosynthesis but is mediated, in part, by its downstream target, interferon regulatory factor 7 (IRF7). Taken together, our study highlights a previously undescribed role of the SREBP2-IRF7 regulatory circuit as a negative feedback loop in osteoclast differentiation and represents a novel mechanism to restrain pathological bone destruction.

TRPA1 aggravates osteoclastogenesis and osteoporosis through activating endoplasmic reticulum stress mediated by SRXN1

Osteoporosis (OP) is a disorder of bone remodeling caused by an imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. Therefore, inhibiting excessive osteoclast activity is one of the promising strategies for treating OP. A major transient receptor potential cation channel, known as transient receptor potential ankyrin 1 (TRPA1), was found to alleviate joint pain and cartilage degeneration in osteoarthritis. However, little research has focused on TRPA1 function in OP. As a result, this study aimed to explore the TRPA1 characteristics and its potential therapeutic function during osteoclastogenesis. The TRPA1 expression gradually increased in the osteoclast differentiation process; however, its suppression with small interfering RNA and an inhibitor (HC030031) significantly controlled the osteoclast count and the expression of osteoclast characteristic genes. Its suppression also inhibited endoplasmic reticulum (ER) stress-related pancreatic ER kinase (PERK) pathways. An ER stress inhibitor (thapsigargin) reversed the down-regulated levels of ER stress and osteoclast differentiation by suppressing TRPA1. Transcriptome sequencing results demonstrated that TRPA1 negatively regulated reactive oxygen species (ROS) and significantly increased the expression of an antioxidant gene, SRXN1. The osteoclast differentiation and the levels of ER stress were enhanced with SRXN1 inhibition. Finally, TRPA1 knockdown targeting macrophages by adeno-associated virus-9 could relieve osteoclast differentiation and osteopenia in ovariectomized mice. In summary, silencing TRPA1 restrained osteoclast differentiation through ROS-mediated down-regulation of ER stress via inhibiting PERK pathways. The study also indicated that TRPA1 might become a prospective treatment target for OP.

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.

Anti-RANKL Antibody For Active Charcot Foot Neuro-Osteoarthropathy in Patients with Diabetes and Chronic Kidney Disease.

Charcot neuroosteoarthropathy (CNO) is characterized with increased osteoclastic activity that can be curbed with antiresorptive agents. Chronic kidney disease (CKD) precludes bisphosphonates but anti-receptor activator of nuclear factor-B ligand (anti-RANKL) antibody, denosumab, can be contemplated in CKD. We investigated denosumab for active CNO of foot in CKD for CNO remission. During the study period, 446 persons of diabetes with unilateral, active CNO of foot and CKD were identified and 78 were finally enrolled. Patients received either 60 mg denosumab (single-dose, subcutaneous) along with standard of care (SoC) as total contact cast (TCC) (group A; n = 26) or SoC (group B; n = 52) only. Patients were followed every 4 weeks until CNO remission and subsequently every 8 weeks until 48 weeks following remission. Remission was defined as temperature difference <2 °C between 2 feet confirmed twice (4 weeks apart) with clinical resolution of signs of inflammation. The primary outcome studied was proportion of patients achieving remission within 48 weeks and the time to remission. Median age was 56.5 (48.8-65) and 57 (48.5-61.2) years, P = .57; duration of diabetes 16 (10-25.3) and 14.9 (10-19) years, P = .151; and estimated glomerular filtration rate 44.8 (21.1-65.6) and 45.7 (32.9-55.7) mL/min/1.73 m2, P = .771, in group A and B, respectively. Median temperature difference at presentation between the affected and opposite foot was 3.4 °C (2.7-6.9) and 3.2 °C (2.2-4.0), P = .119, respectively. All patients achieved remission in group A (100%) compared with 42 (80.8%) in group B (P = .006) (hazard ratio 0.52, 95% CI: 0.32-0.87; P = .012). The median time to remission was similar in the 2 groups (15 [11-25] and 17.5 [14-31.5] weeks, P = .229, respectively). 25-Hydroxyvitamin D3 >14 ng/mL was significantly associated (OR 9.5, 95% CI 1.04-87.5, P = .045) with remission. Anti-RANKL antibody added to SoC (TCC) induces remission of active foot CNO in greater proportions of patients with diabetes and CKD.

Effects of cluster set resistance training on bone mineral density and markers of bone metabolism in older hemodialysis subjects: A pilot study

Chronic kidney disease (CKD) is associated with a series of mineral bone disturbances due to increased production of parathormone which increases the activity of osteoclasts, removing calcium and phosphorous from the bones. However, the literature lacks investigations on the feasibility of different resistance training (RT) methods, such as cluster-sets, in this population. Thus, the aim of the present study was to compare traditional versus cluster-set RT protocols on bone mineral density (BMD) T-score, BMD Total, femur BMD, L3-L4 BMD, femoral neck BMD, Klotho, FGF23, Klotho - FGF23 ratio, Sclerostin, vitamin D, phosphorous and calcium in older subjects with CKD. Seventy-eight older subjects (age: 57.55 ± 4.06 years, body mass: 72.26 ± 13.96 kg, body mass index: 26.73 ± 2.97 kg/m2) with CKD undergoing maintenance hemodialysis were randomly divided into control group (CG, n = 26), traditional RT (RT, n = 26) and cluster-set RT (RT-CS, n = 26) groups. Subjects completed 24 weeks of RT three times per week, 1 h and 30 min before the hemodialysis session, and each training lasted around 60 to 80 min. There was a group×time interaction for total BMD, femur BMD, L3-L4 BMD, and femoral neck BMD, revealed by improvements for RT and RT-CS groups (pre versus post). Only femur BMD displayed differences as compared with the CG. Minimum clinically important difference (MCID) values revealed more responsive subjects in the RT-CS group for total BMD, femur BMD, klotho, FGF23, sclerostin, Vitamin D and calcium. In conclusion, RT can be used as a non-pharmacological complementary strategy for the treatment of CKD. RT-CS may be useful for these subjects as more responders were found for this type of training.

Increase in major osteoporotic fractures after therapy with immune checkpoint inhibitors

BackgroundImmune checkpoint inhibitors (ICIs) can cause severe and sometimes long-standing immune-related adverse events (irAEs). Enhanced immune activation from ICI can theoretically result in osteoclast activation, bone loss and fracture. The...

A natural agent, 5-deoxycajanin, mitigates estrogen-deficiency bone loss via modulating osteoclast-osteoblast homeostasis

Hyperactive osteoclasts and hypoactive osteoblasts usually result in osteolytic conditions such as estrogen-deficiency bone loss. Few natural compounds that both attenuating bone resorption and enhancing bone formation could exert effects on this imbalance. 5-Deoxycajanin (5-D), an isoflavonoid extracted from Cajan leaf with estrogen-like properties, were found to have beneficial pharmacological effects on rebalancing the activities of osteoclasts and osteoblasts. This study revealed that 5-D at the same concentration could inhibit osteoclastogenesis of BMMs and promoted osteoblast differentiation of BMSCs. 5-D not only attenuated the fluorescent formation of RANKL-induced F-actin belts and NFATc1, but also activated ALP and RUNX2 expressions. As to downstream factor expressions, 5-D could block osteoclast-specific genes and proteins including NFATc1 and CTSK, while increased osteogenic genes and proteins including OPG and OCN, as confirmed by Real-time PCR and Western Blotting. Additionally, the network pharmacology and molecular docking identified the involvement of 5-D in the MIF and MAPK signaling pathways and the stable binding between 5-D and MAPK2K1. Further Western blot studies showed that 5-D decreased the phosphorylation of p38 and ERK in osteoclasts, but promoted these phosphorylations in osteoblasts. In a female C57BL/6J mouse model of estrogen deficiency-induced bone loss, 5-D demonstrated efficacy in enhancing BMD through attenuating osteoclast activities and promoting osteogenesis. These results underscore the potential application of 5-D on treating osteolysis resulting from hyperactive osteoclasts and hypoactive osteoblasts, shedding light on modulating osteoclast-osteoblast homeostasis.

The Effects of Chronic Psychostimulant Administration on Bone Health: A Review.

(1) Background: Methylphenidate (MP) and amphetamine (AMP) are psychostimulants that are widely prescribed to treat Attention Deficit Hyperactivity Disorder (ADHD) and narcolepsy. In recent years, 6.1 million children received an ADHD diagnosis, and nearly 2/3 of these children were prescribed psychostimulants for treatment. The purpose of this review is to summarize the current literature on psychostimulant use and the resulting effects on bone homeostasis, biomechanical properties, and functional integrity. (2) Methods: Literature searches were conducted from Medline/PubMed electronic databases utilizing the search terms "methylphenidate" OR "amphetamine" OR "methylphenidate" AND "bone health" AND "bone remodeling" AND "osteoclast" AND "osteoblast" AND "dopamine" from 01/1985 to 04/2023. (3) Results: Of the 550 publications found, 44 met the inclusion criteria. Data from identified studies demonstrate that the use of MP and AMP results in decreases in specific bone properties and biomechanical integrity via downstream effects on osteoblasts and osteoclast-related genes. (4) Conclusions: The chronic use of psychostimulants negatively affects bone integrity and strength as a result of increased osteoclast activity. These data support the need to take this into consideration when planning the treatment type and duration for bone fractures.

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.

Biomodulation effects induced by ultrasound stimulation in periodontal cells implicated in orthodontic tooth movement: A systematic review.

Accelerating orthodontic tooth movement (OTM) is increasingly important for shorter treatment times, which reduces periodontal risks, root resorption and dental caries. Techniques to accelerate OTM focus on stimulating bone remodelling by enhancing osteoclast and osteoblast activity and include both surgical and non-surgical methods. The therapeutic potential of ultrasounds is highly recognized among many medical areas and has shown promising results in modulating bone remodelling and inflammation phenomena. This systematic review aims to collect and analyse the current scientific invitro and exvivo evidence on ultrasound stimulation (US) bioeffects in cells implicated in tooth movement. This review was conducted according to PRISMA 2020 guidelines. A bibliographic search was carried out in the PubMed, Scopus and Web of Science databases. Sixteen articles were selected and included in this review. The revised studies suggest that US of 1.0 and 1.5 MHz, delivered at 30 mW/cm2, 10 to 30 min daily over three to 14 days seems to be effective in promoting osteoclastogenic activity, while US of 1.5 MHz, 30 to 90 mW/cm2, in 5- to 20-min sessions delivered daily for 5 to 14 days exhibits the potential to stimulate osteogenic activity and differentiation. Previous research yielded varied evidence of the effectiveness of US in orthodontics. Future animal studies should employ the recommended US parameters and investigate how distinct protocols can differentially impact tissue remodelling pathways. The knowledge arising from this review will ultimately potentiate the application of US to accelerate OTM in the clinical setting.

Multi-omics analyses reveal aberrant differentiation trajectory with WNT1 loss-of-function in type XV osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a group of severe genetic bone disorders characterized by congenital low bone mass, deformity, and frequent fractures. Type XV OI is a moderate to severe form of skeletal dysplasia caused by WNT1 variants. In this cohort study from southern China, we summarized the clinical phenotypes of patients with WNT1 variants and found that the proportion of type XV patients was around 10.3% (25 out of 243) with a diverse spectrum of phenotypes. Functional assays indicated that variants of WNT1 significantly impaired its secretion and effective activity, leading to moderate to severe clinical manifestations, porous bone structure, and enhanced osteoclastic activities. Analysis of proteomic data from human skeleton indicated that the expression of SOST (sclerostin) was dramatically reduced in type XV patients compared to patients with COL1A1 quantitative variants. Single-cell transcriptome data generated from human tibia samples of patients diagnosed with type XV OI and leg-length discrepancy, respectively, revealed aberrant differentiation trajectories of skeletal progenitors and impaired maturation of osteocytes with loss of WNT1, resulting in excessive CXCL12+ progenitors, fewer mature osteocytes, and the existence of abnormal cell populations with adipogenic characteristics. The integration of multi-omics data from human skeleton delineates how WNT1 regulates the differentiation and maturation of skeletal progenitors, which will provide a new direction for the treatment strategy of type XV OI and relative low bone mass diseases such as early onset osteoporosis.