Glycogen synthase kinase 3-beta (GSK3β) is a highly conserved protein kinase originally involved in glucose metabolism, insulin activity, and energy homeostasis. Recent scientific evidence demonstrated the significant role of GSK3β in regulating bone remodelling through involvement in multiple signalling networks. Specifically, the inhibition of GSK3β enhances the conversion of osteoclast progenitors into mature osteoclasts. GSK3β is recognised as a pivotal regulator for the receptor activator of nuclear factor-kappa B (RANK)/receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin (OPG), phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT), nuclear factor-kappa B (NF-κB), nuclear factor-erythroid 2-related factor 2 (NRF2)/Kelch-like ECH-associated protein 1 (KEAP1), canonical Wnt/beta (β)-catenin, and protein kinase C (PKC) signalling pathways during osteoclastogenesis. Conversely, the inhibition of GSK3β has been shown to prevent bone loss in animal models with complex physiology, suggesting that the role of GSK3β may be more significant in bone formation than bone resorption. Divergent findings have been reported regarding the efficacy of GSK3β inhibitors as bone-protecting agents. Some studies demonstrated that GSK3β inhibitors reduced osteoclast formation, while one study indicated an increase in osteoclast formation in RANKL-stimulated bone marrow macrophages (BMMs). Given the discrepancies observed in the accumulated evidence, further research is warranted, particularly regarding the use of GSK3β silencing or overexpression models. Such efforts will provide valuable insights into the direct impact of GSK3β on osteoclastogenesis and bone resorption.

OBJECTIVE: This study aimed to verify whether there is a difference in biomarker levels in the gingival crevicular fluid between premenopausal and postmenopausal women undergoing orthodontic treatment.
METHODS: As eligibility criteria, prospective or retrospective observational studies evaluating women undergoing orthodontic treatment (P), comparing postmenopausal (E) and premenopausal (C) women, and analyzing differences in gingival crevicular fluid biomarkers (O) were included. An electronic search was conducted in seven databases (PubMed, Scopus, Web of Science, LILACS, The Cochrane Library, Embase, and EBSCO: Dentistry & Oral Science) and one grey literature source (Google Scholar). All databases were searched from September 2022 to March 2023. After duplicate exclusion and data extraction, the Newcastle-Ottawa scale was applied to assess the quality and risk of bias, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool was used to verify the certainty of evidence.
RESULTS: Three case-control studies that analyzed receptor activator of nuclear factor kappa‑B ligand (RANKL), osteopontin (OPN), and interleukin (IL)-17A levels were included. One study reported a significant difference for RANKL and another for OPN levels. A third study reported that there was a higher expression of IL17‑A in the postmenopausal group. However, the small number of articles limits our systematic review. The heterogeneity and imprecision in the study results cast doubt on the findings\' internal validity.
CONCLUSIONS: The studies reported alterations in biomarker levels but differed in their conclusions. Therefore, further studies must include other types of bone and inflammatory biomarkers in female patients who are pre- or postmenopausal and undergoing orthodontic treatment.
BACKGROUND: The review was registered at the Open Science Framework ( https://doi.org/10.17605/OSF.IO/Q9YZ8 ).
UNASSIGNED: ZIELSETZUNG: In dieser Studie sollte überprüft werden, ob es einen Unterschied in den Biomarkerkonzentrationen in der Sulkusflüssigkeit zwischen prämenopausalen und postmenopausalen Frauen gibt, die sich einer kieferorthopädischen Behandlung unterziehen.
METHODS: Als Auswahlkriterien wurden prospektive oder retrospektive Beobachtungsstudien einbezogen, in denen Frauen untersucht wurden, die sich einer kieferorthopädischen Behandlung unterzogen (P), in denen postmenopausale (E) und prämenopausale (C) Frauen verglichen wurden und in denen Unterschiede in den Biomarkern in der Sulkusflüssigkeit analysiert wurden (O). Es wurde eine elektronische Suche in 7 Datenbanken durchgeführt (PubMed, Scopus, Web of Science, LILACS, The Cochrane Library, Embase und EBSCO:Dentistry & Oral Science) und einer Quelle für graue Literatur (Google Scholar) durchgeführt. Alle Datenbanken wurden von September 2022 bis März 2023 durchsucht. Nach Duplikatsausschluss und Datenextraktion wurden die Newcastle-Ottawa-Skala zur Bewertung von Qualität und Bias-Risiko angewandt und das GRADE-Tool (Grading of Recommendations Assessment, Development and Evaluation) zur Überprüfung der Evidenzsicherheit.
UNASSIGNED: Einbezogen wurden 3 Fall-Kontroll-Studien, in denen die Spiegel von RANKL („receptor activator of nuclear factor kappa‑B ligand“), OPN (Osteopontin) und IL(Interleukin)-17A verglichen worden waren. Eine Studie berichtete über einen signifikanten Unterschied bei den RANKL- und eine andere bei den OPN-Werten. Eine dritte Studie berichtete über eine höhere Expression von IL-17A in der Gruppe der postmenopausalen Frauen. Die geringe Anzahl von Veröffentlichungen schränkt jedoch unsere systematische Überprüfung ein. Die Heterogenität und Ungenauigkeit der Studienergebnisse lassen Zweifel an der internen Validität der Ergebnisse aufkommen.
UNASSIGNED: Die Studien berichteten über Veränderungen der Biomarkerspiegel, kamen jedoch zu unterschiedlichen Schlussfolgerungen. Daher müssen weitere Studien andere Arten von Knochen- und Entzündungsbiomarkern bei prä- oder postmenopausalen Patientinnen einbeziehen, die sich einer kieferorthopädischen Behandlung unterziehen.
UNASSIGNED: Der Review wurde beim Open Science Framework ( https://doi.org/10.17605/OSF.IO/Q9YZ8 ) registriert.

OBJECTIVE: The OPG/RANKL signal pathway was important regulation mechanism of bone remodeling cycle, but the effect of osteoprotegerin (OPG) and RANKL in osteoporosis was uncertain. We did a systematic review with meta-analysis to assess the association between serum OPG/RANKL and osteoporosis.
METHODS: The systematic search, data extraction, critical appraisal, and meta-analysis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Randomized controlled studies were searched in PubMed, OvidMedline, Embase (1946 to present). Standard mean difference (SMD), and associated credible interval (CI) were calculated using RevMan statistical software to assess the continuous data. Heterogeneity in studies was measured by I2 values. Subgroup analysis was performed based on different bone turnover.
RESULTS: A total of 5 randomized controlled studies met the inclusion criteria. Both OPG and RANKL had no significant differences between the osteoporosis and control group, and the statistical heterogeneity was high in meta-analysis. However, RANKL had significant differences between the osteoporosis group with low bone turnover and control group (SMD =  - 1.17; 95% CI - 1.77 to 0.57; P value < 0.01) in subanalysis. Furthermore, the OPG/RANKL ratio was significant lower in the osteoporosis group than in the control group (SMD =  - 0.29; 95% CI - 0.57 to - 0.02; P value < 0.05), and the statistical heterogeneity was very low (Chi2 = 0.20, P = 0.66, I2 = 0%).
CONCLUSIONS: Our meta-analysis study supported OPG and RANKL were important modulatory factors of bone formation and resorption in bone turnover, respectively. Although the serum level of both OPG and RANKL were not associated with osteoporosis, but the OPG/RANKL ratio was associated with osteoporosis. In future, standardizing the test method and unit was good to clinical application.

A common type of cancer among men is the prostate cancer that kills many people every year. The multistage of this disease and the involvement of the vital organs of the body have reduced the life span and quality of life of the people involved and turned the treatment process into a complex one. NFATc1 biomarker contributes significantly in the diagnosis and treatment of this disease by increasing its expression in prostate cancer and helping the proliferation, differentiation, and invasion of cancer cells through different signaling pathways. NFATc1 is also able to target the metabolism of cancer cells by inserting specific oncogene molecules such as c-myc that it causes cell growth and proliferation. Bone is a common tissue where prostate cancer cells metastasize. In this regard, the activity of NFATc1, through the regulation of different signaling cascades, including the RANKL/RANK signaling pathway, in turn, increases the activity of osteoclasts, and as a result, bone tissue is gradually ruined. Using Silibinin as a medicinal plant extract can inhibit the activity of osteoclasts related to prostate cancer by targeting NFATc. Undoubtedly, NFATc1 is one of the effective oncogenes related to prostate cancer, which has the potential to put this cancer on the path of progression and metastasis. In this review, we will highlight the role of NFATc1 in the progression and metastasis of prostate cancer. Furthermore, we will summarize signaling pathways and molecular mechanism, through which NFATc1 regulates the process of prostate cancer.

Giant cell tumor (GCT) of the bone is a locally aggressive primary bone tumor, that can rarely metastasize. Arising mostly in epiphysis of the long bones in young adults, the tumor is composed of mononuclear cells that are admixed with osteoclastic giant cells(OLGCs), which express RANK ligand and RANK respectively. Denosumab a monoclonal antibody against RANK ligand has been shown to reduce the tumor by causing bone lysis by inhibiting RANKL. Histological changes in 11 patients of GCT who were treated with denosumab are presented here.
Clinical records and slides of 11 patients of GCT who had been administered neoadjuvant denosumab were included in the study. Evaluation of pre and post therapy GCT specimens was performed by two pathologists (RK and VM). There were 4 males and 7 females. Their mean age was 30 years. All the patients received 120 mg denosumab subcutaneously every week with additional 120 mg on days 8 and 15 of therapy. The histological slides were reviewed and following points noted: 1) degree of ossification,2) fibrosis,3) loss of osteoclastic giant cells,4) proliferation of mononuclear cells,5) atypia,6) Permeation of osteoid by malignant cells.
Out of 11 cases, 2 cases did not show any significant histological improvement. 7 cases showed reduction in giant cells, increased fibrosis, enhanced mononuclear cell proliferation and ossification consistent with a pathological response. Atypia and osteoid permeation were noted in 2 cases which showed transformation to osteosarcoma.
Denosumab treated giant cell tumor show dramatic histological changes. The post therapy lesions may bear no resemblance to pretherapy lesion. There may be complete resolution or may be confused with benign or malignant lesions Rarely they may show sarcomatous transformation. It is imperative that the pathologist is aware of these changes to prevent diagnostic pitfalls as it poses therapeutic and prognostic implications.

Denosumab is a human monoclonal antibody indicated for patients with osteoporosis and a high risk of fractures. It targets RANKL, the receptor activator of NF-κB (RANK) ligand, blocking RANKL-RANK interaction and leading to rapid osteoclast-mediated bone resorption inhibition. But RANK is widely expressed in neurons, microglia, and astrocytes. RANKL/RANK/NF-κB system can play an important role in the neuroinflammatory response, depressive behavior, memory impairments, and neurotrophism. We present two well-documented case reports of recurrent neuropsychiatric manifestations in patients treated with denosumab and a descriptive review of similar cases reported to the Food and Drug Administration Adverse Event Reporting System (FAERS) database between 2012 and 2022. Only those reported by healthcare professionals, coding denosumab as the only suspected drug, were retained. An 81-year-old woman with pre-existing mild cognitive impairment suffered two acute confusional episodes and another 81-year-old woman with depression in remission suffered two depressive recurrences with anxiety and psychomotor inhibition, in both cases following sequential administrations of denosumab without underlying calcium/phosphate imbalance. Scores on Naranjo Adverse Drug Reaction Probability Scale were 6 and 7, respectively, suggesting a probable causal relationship. Of the 91,151 cases with denosumab exposure reported to FAERS, 5.7% were related to psychiatric/neurological disorders and 23.8% of these corresponded to cognitive impairment, depressive/mood disturbances, or psychomotor retardation. Denosumab may cause transient but severe neuropsychiatric symptoms by several mechanisms involving RANKL blockade and subsequent immuno-inflammatory changes, at least in subjects with pre-existing neurobiological vulnerability. We recommend caution and careful monitoring of these patients following denosumab administrations.

Zinc is a micronutrient of key importance for human health. An increasing number of studies indicate that zinc plays a significant role in bone tissue\'s normal development and maintaining homeostasis. Zinc is not only a component of bone tissue but is also involved in the synthesis of the collagen matrix, mineralization, and bone turnover. It has been demonstrated that zinc can stimulate runt-related transcription factor 2 (Runx2) and promote the differentiation of osteoblasts. On the other hand, zinc has been found to inhibit osteoclast-like cell formation and to decrease bone resorption by stimulating osteoclasts\' apoptosis. Moreover, zinc regulates the RANKL/RANK/OPG pathway, thereby facilitating bone remodeling. To date, not all mechanisms of Zn activity on bone tissue are well understood and documented. The review aimed to present the current state of research on the role of zinc in bone tissue, its beneficial properties, and its effects on bone regeneration. Since calcium phosphates as bone substitute materials are increasingly enriched in zinc ions, the paper included an overview of research on the potential role of such materials in bone filling and regeneration.

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Osteoclastogenesis is an ongoing rigorous course that includes osteoclast precursors fusion and bone resorption executed by degradative enzymes. Osteoclastogenesis is controlled by endogenous signaling and/or regulators or affected by exogenous conditions and can also be controlled both internally and externally. More evidence indicates that autophagy, inflammation, and immunity are closely related to osteoclastogenesis and involve multiple intracellular organelles (e.g., lysosomes and autophagosomes) and certain inflammatory or immunological factors. Based on the literature on osteoclastogenesis induced by different regulatory aspects, emerging basic cross-studies have reported the emerging disquisitive orientation for osteoclast differentiation and function. In this review, we summarize the partial potential therapeutic targets for osteoclast differentiation and function, including the signaling pathways and various cellular processes.

The drugs used for treating bone diseases (BDs), at present, elicit hazardous side effects that include certain types of cancers and strokes, hence the ongoing quest for the discovery of alternatives with little or no side effects. Natural products (NPs), mainly of plant origin, have shown compelling promise in the treatments of BDs, with little or no side effects. However, the paucity in knowledge of the mechanisms behind their activities on bone remodeling has remained a hindrance to NPs\' adoption. This review discusses the pathological development of some BDs, the NP-targeted components, and the actions exerted on bone remodeling signaling pathways (e.g., Receptor Activator of Nuclear Factor κ B-ligand (RANKL)/monocyte/macrophage colony-stimulating factor (M-CSF)/osteoprotegerin (OPG), mitogen-activated protein kinase (MAPK)s/c-Jun N-terminal kinase (JNK)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), Kelch-like ECH-associated protein 1 (Keap-1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/Heme Oxygenase-1 (HO-1), Bone Morphogenetic Protein 2 (BMP2)-Wnt/β-catenin, PhosphatidylInositol 3-Kinase (PI3K)/protein kinase B (Akt)/Glycogen Synthase Kinase 3 Beta (GSK3β), and other signaling pathways). Although majority of the studies on the osteoprotective properties of NPs against BDs were conducted ex vivo and mostly on animals, the use of NPs for treating human BDs and the prospects for future development remain promising.