Bone Disease Research Articles

DOMINÓ Registry: study protocol on mineral and bone disease (DOença MINeral e Óssea) of chronic kidney disease in pediatrics in Brazil.

Pediatric patients with chronic kidney disease (CKD) develop mineral and bone disorders (MBD). We do not have Brazilian data that evaluate these outcomes, which can be obtained through epidemiological records. To present the DOMINÓ study, which aims to describe CKD-MBD characteristics in Brazilian pediatric patients. Retrospective and prospective, multicenter, observational cohort. The retrospective study will analyze data from prevalent patients in 2024, and the prospective study will analyze data from 2025 onwards. Demographic, clinical, laboratory, imaging, and bone biopsy data will be collected from pediatric patients with CKD-MBD < 18 years old with CKD stage 3-5D and kidney transplant recipients. The Ethics Committees of the participating centers approved the study. The DOMINÓ study will provide information on the incidence, prevalence, morbidity, treatment results, and mortality of this pediatric disease in Brazil. Future analyses will allow us to identify predictors of response to treatment and improve the care for these patients.

Sarcopenic obesity is attenuated by E-syt1 inhibition via improving skeletal muscle mitochondrial function.

In aging and metabolic disease, sarcopenic obesity (SO) correlates with intramuscular adipose tissue (IMAT). Using bioinformatics analysis, we found a potential target protein Extended Synaptotagmin 1 (E-syt1) in SO. To investigate the regulatory role of E-syt1 in muscle metabolism, we performed in vivo and in vitro experiments through E-syt1 loss- and gain-of-function on muscle physiology. When E-syt1 is overexpressed in vitro, myoblast proliferation, differentiation, mitochondrial respiration, biogenesis, and mitochondrial dynamics are impaired, which were alleviated by the silence of E-syt1. Furthermore, overexpression of E-syt1 inhibited mitophagic flux. Mechanistically, E-syt1 overexpression leads to mitochondrial calcium overload and mitochondrial ROS burst, inhibits the fusion of mitophagosomes with lysosomes, and impedes the acidification of lysosomes. Animal experiments demonstrated the inhibition of E-syt1 increased the capacity of endurance exercise, muscle mass, mitochondrial function, and oxidative capacity of the muscle fibers in OVX mice. These findings establish E-syt1 as a novel contributor to the pathogenesis of skeletal muscle metabolic disorders in SO. Consequently, targeting E-syt1-induced dysfunction may serve as a viable strategy for attenuating SO.

Development of a natural rubber latex-based biodevice with mesenchymal stem cells as a potential treatment for skeletal muscle regeneration in gestational diabetes-induced myopathy.

Women with gestational diabetes mellitus show a high risk of developing Gestational Diabetes Induced Myopathy (GDiM). GDiM is characterized by significant pelvic floor skeletal muscle atrophy and urinary incontinence. This study aimed to develop a natural rubber latex (NRL) based biodevice with mesenchymal/stromal stem cells (MSCs) for skeletal muscle regeneration for women with GDiM. NRL showed porosity, roughness, biocompatibility, and bioactivity. MSCs adhesion on the NRL scaffold surface was assessed by scanning electron microscopy (SEM), confocal microscopy, and zymography. The scaffold's physicochemical and biological properties were carried out by Fourier transform infrared spectroscopy (FTIR), swelling and degradation studies, hemolytic activity, and antioxidant activity (AA), using Electronic Paramagnetic Resonance (EPR). MSCs in culture expressed CD90, adhered to plastic, differentiated, and produced fibroblast colonies. A high rate of cell proliferation was seen in MSCs on the NRL scaffold. FTIR analysis confirmed protein structures and polyisoprene in the scaffold. Swelling and degradation showed low water uptake and weight loss. Furthermore, NRL presented a hemolytic rate of 2.90±0.26% for 24h, and EPR revealed the scaffold's strong AA. The generated biodevice has potential for muscle regeneration and may be useful as a therapeutic option for skeletal muscle disorders in GDiM or urinary incontinence.

Using CT imaging to identify sarcopenia as a risk factor for severe falls in older adults.

Sarcopenia is a skeletal muscle disease primarily associated with ageing and progressive muscle decline and increases the risk of falls. The purpose of the present study was to investigate risk factors, including sarcopenia, for severe falls compared to non-severe falls. In addition, we wanted to explore possible associations between sarcopenia, bone mineral density (BMD), adipose tissue as well as clinical scores assessing frailty, nutritional status, and fall risk. This retrospective cohort study included 101 older patients that had experienced a fall incident during in-patient care at a geriatric ward between 2018 and 2020. The fall incidents were categorized into severe or non-severe falls. Clinical data, including risk assessment scores were retrospectively obtained from the participants' medical records. Body composition, including skeletal muscle quantity (SKM), adipose tissues, and BMD were assessed from abdominal CT-scans performed for any reason maximal 6 months before or after the fall. Skeletal muscle index ratio (SMI-ratio) was calculated using SKM cm2/height m2 and divided with previous described cut off values for sarcopenia. An SMI ratio < 100% indicated sarcopenia. The severe fall group showed higher grade of sarcopenia compared to the non-severe fall group (SMI ratio of 71% vs. 83%, p = 0.041) as well as lower, though statistically non-significant, BMI and subcutaneous adipose tissue (SAT) (BMI 22 [20-24] vs. 24 [22-27] kg/m2, p = 0.108, and SAT 95 ± 70cm² vs. 141 ± 94cm², p = 0.124). Overweight was more common in non-severe than severe fall group (43% vs. 14%, p = 0.048). SMI ratio correlated negatively with frailty and positive with BMI and the following body composition measurements: intramuscular-, subcutaneous, and visceral adipose tissue (IMAT, SAT and VAT). No correlation with other clinical risk assessment scores nor spine T-score was found. In the multivariate analysis, higher level of frailty, male sex as well as lower BMI, VAT and SAT remained as risk factors for low SMI ratio. These results underscore the importance of addressing sarcopenia and related risk factors, including malnutrition, in the management and prevention of severe falls in the elderly population. Body composition analyzed in CT-scans could add value in this risk assessment. This analysis could be conducted opportunistically during CT scans performed for other purposes.

Exploring the application of herbal photosensitizers in antimicrobial photodynamic therapy against Mycobacterium Tuberculosis.

Tuberculosis (TB) is one of the leading causes of death in the world, despite being a preventable and curable disease. Irrespective of tremendous advancements in early detection and treatment, this disease still has high mortality rates. This is due to the development of antibiotic resistance, which significantly reduced the efficacy of antibiotics, rendering them useless against this bacterial infection. This, in turn, causes immune system evasion, antibiotic treatment failures, and recurrence of disease in patients. Regarding this, photodynamic inactivation (PDI) may serve as a useful substitute for antibiotic therapy against drug-resistant mycobacteria.This century-old therapy is already being used in cancer treatment, dentistry, and skeletal and cardiovascular diseases, but it is not yet used in tuberculosis treatment. Researchers have previously used PDI to eradicate other members of the genus Mycobacteria in both in vitro and in vivo settings. This suggests PDI can be explored against M. tuberculosis too. The one limitation associated with PDI is the use of chemical photosensitizers, which are fatal to normal tissues and induce side effects. Recent studies suggest herbal photosensitizers are equally potent as chemically synthesized ones. Therefore, herbal photosensitizers could be used to solve the problem because of their less toxicity to healthy tissues and decreased frequency of side effects.This review emphasizes the importance of herbal photosensitizers and their role as anti-tuberculosis drugs in PDI therapy and also presents five potential herbal photosensitizers-curcumin, quercetin, resveratrol, aloe emodin, and phloretin that could be utilized in the clinical development of PDT-mediated tuberculosis therapies.

681 Metabolic bone disease in extremely preterm infants: risk factors and outcomes

681 Metabolic bone disease in extremely preterm infants: risk factors and outcomes

Long non-coding RNA NRIR inhibits osteogenesis in peri-implantitis by promoting NLRP3 inflammasome-mediated macrophage pyroptosis.

Peri-implantitis is an inflammatory bone disease that seriously affects the health of dental implants. Pyroptosis plays an important role in peri-implantitis and inhibition of pyroptosis may point out a new direction for treating the disease. The long non-coding RNA Negative Regulator of Interferon Response (lncRNA NRIR) is closely related to peri-implantitis and may be involved in the process of pyroptosis. The aim of this study was to explore the regulatory mechanism of NRIR in peri-implantitis. The expression levels of NRIR and its target gene Cytidine Monophosphate Kinase 2 (CMPK2) in the gingiva surrounding infected implants were explored using bioinformatics analysis. Lipopolysaccharide (LPS)-stimulated macrophage pyroptosis model and a rat model of LPS-induced peri-implantitis were constructed. We used small interfering RNA (siRNA) and plasmids to regulate the expression of NRIR and CMPK2 in macrophages. We used various ways to evaluate inflammation, pyroptosis, osteogenic differentiation, including RT-qPCR, Western blotting, ELISA, Immunofluorescence staining, ALP activity, ARS staining, and Immunohistochemical analysis. Initially, we used bioinformatics method to identify high expression of NRIR and CMPK2 in the gingiva surrounding infected implants. Both the knockdown of NRIR and CMPK2 could markedly suppress the expression of NLRP3 inflammasome and the release of interleukin-1β (IL-1β) in LPS-stimulated THP-1-derived macrophages. Meanwhile, upregulation of CMPK2 reversed the negative effects of downregulation of NRIR on macrophage pyroptosis. Functionally, NRIR knockdown in macrophages promoted osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Notably, we identified that IL-1β protein could reverse this trend. Mechanistically, NRIR regulated NLRP3 inflammasome-mediated pyroptosis of macrophages through the NF-κB pathway. Furthermore, the in vivo experiments demonstrated that silencing NRIR inhibited the expression of NLRP3 inflammasome and IL-1β, but promoted the expression of osteogenic differentiation related factors in tissue surrounding the implants. This study demonstrated that NRIR played a crucial role in the crosstalk between macrophage pyroptosis and BMSCs osteogenic differentiation, thus providing a possible therapeutic target against inflammatory bone disease including peri-implantitis.

Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD) in Pediatric Kidney Transplant Recipients.

Kidney transplantation remains the gold standard treatment for end-stage kidney disease (ESKD), effectively alleviating numerous comorbidities and offering a substantial survival advantage over long-term dialysis. Despite advancements in immunosuppressive regimens and improvements in graft and patient survival rates, extended patient longevity brings an accumulating burden and complexity of bone disease in this population, which often goes underrecognized. The present study reviews the pathophysiology of CKD-MBD in pediatric KTR, focusing on the progression of bone disease before and after transplantation. We aim to enhance understanding of available screening options, highlighting their advantages and limitations, to support more informed decision-making in CKD-MBD management.

Investigating the molecular mechanisms of Jiangu Decoction in treating type 2 diabetic osteoporosis.

Type 2 diabetic osteoporosis (T2DOP) is a metabolic bone disease characterized by impaired bone structure and decreased bone strength in diabetic patients. Jiangu Decoction (JGD), a traditional Chinese poly-herbal formulation, has shown efficacy in mitigating osteoporosis (OP) and fractures caused by osteoporosis in diabetic patients in clinical trials. In addition, JGD has been proven to promote the proliferation of osteoblasts. However, the specific mechanisms underlying these effects remain unclear. This study aimed to elucidate the molecular mechanisms underlying the therapeutic effects of JGD in treating T2DOP. Liquid chromatography-mass spectrometry (LC-MS) was utilized to elucidate the chemical profile of JGD. A T2DOP mouse model (C57BL/6) was established by combining a high-fat diet with streptozotocin (STZ). Micro-computed tomography (micro-CT) imaging, three-point bending tests, and histological staining were utilized to assess alterations in bone mass, bone quality, and bone strength in mice. Mouse Calvaria 3T3-E1 (MC3T3-E1) cells were treated with 33mmol/L D-glucose (HG), and the protective effect of JGD on the high glucose injury model was observed. Western blotting and qRT-PCR were employed to analyze alterations in biomarkers associated with the Keap1/Nrf2/HO-1 signaling pathway, both in vivo and in vitro. A total of 909 compounds were identified in JGD using LC-MS. Subsequently, the function of JGD was evaluated both in vitro and in vivo. The findings indicated that JGD promoted bone formation, enhanced bone microstructure, and ameliorated diabetic symptoms in T2DOP mice. Additionally, JGD increased alkaline phosphatase (ALP) activity, facilitated bone mineralization, and upregulated the expression levels of osteogenic marker genes such as runt-related transcription factor 2 (Runx2), osteocalcin (Ocn), and collagen type 1 alpha (Col1a1). Importantly, JGD reduced oxidative stress levels and decreased the accumulation of reactive oxygen species by modulating the Keap1/Nrf2/HO-1 axis both in vivo and in vitro. Our study suggests that JGD could alleviate T2DOP impairment, closely linked to the Keap1/Nrf2/HO-1 signaling pathway.

Prevalence and Determinants of Sarcopenia Among Older Adults in India: Insights From the Longitudinal Aging Study in India.

Sarcopenia, characterized by declining muscle mass and function, is a growing concern among India's aging population. This study investigates sarcopenia's prevalence and determinants using the nationally representative LASI dataset. This analysis included 26,780 community-dwelling adults aged 60 and above, with informed consent obtained from all participants. Sarcopenia was defined using the Asian Working Group for Sarcopenia (AWGS) 2019 criteria. Demographic, socioeconomic, health, and geriatric factors, including age, sex, living arrangements, economic status, comorbidities, and geriatric syndromes, were examined. Multinomial logistic regression was used to analyze associations with sarcopenia and severe sarcopenia, and results were expressed as relative risk ratios (RRR) with 95% confidence intervals (CI). The prevalence of sarcopenia was 43.6% (n = 11,665), and 19.4% (n = 5202) had severe sarcopenia. Sociodemographic factors significantly associated with sarcopenia and severe sarcopenia included being widowed (RRR: 1.24, 95% CI: 1.12-1.37 for sarcopenia; RRR: 1.82, 95% CI: 1.64-2.03 for severe sarcopenia) or divorced (RRR: 1.68, 95% CI: 1.12-2.54 for severe sarcopenia). Additionally, a higher BMI and higher education level were associated with a lower risk of sarcopenia. Among comorbidities, joint and bone diseases were linked to both sarcopenia (RRR: 1.21, 95% CI: 1.07-1.35) and severe sarcopenia (RRR: 1.4, 95% CI: 1.23-1.58), while hypertension (RRR: 1.22, 95% CI: 1.1-1.36), chronic lung disease (RRR: 1.22, 95% CI: 1.02-1.44), and cerebrovascular accident (RRR: 1.5, 95% CI: 1.09-2.08) were specifically associated with severe sarcopenia. Geriatric syndromes such as tooth loss, impaired vision and hearing, history of falls, and depression were significantly associated with increased risk of sarcopenia. This study reveals significant associations between sarcopenia and various sociodemographic factors, comorbidities, and geriatric syndromes in older adults in India, suggesting potential areas for targeted intervention. However, further longitudinal studies are needed to validate these findings and clarify the causal relationships of the observed associations.

Defective Cystic Fibrosis Transmembrane Conductance Regulator Accelerates Skeletal Muscle Aging by Impairing Autophagy/Myogenesis.

Regenerative capacity of skeletal muscles decreases with age. Deficiency in cystic fibrosis transmembrane conductance regulator (CFTR) is associated with skeletal muscle weakness as well as epithelial cell senescence. However, whether and how CFTR plays a role in skeletal muscle regeneration and aging were unclear. Vastus lateralis biopsy samples from male and female human subjects (n = 23) of 7- to 86-year-old and gastrocnemii tissues from mice of 4- to 29-month-old were examined for CFTR expression. Skeletal muscle tissues or cultured myoblasts from mice carrying CFTR mutation (DF508) at 4- to 18-month-old were used for assessment of muscle mass, contractile force and regenerative capacity as well as myogenic and autophagy signalling. Overexpression of LC3-β, an autophagy mediator, was conducted to reverse myogenic defects in DF508 myoblasts. Adenoviruses containing CFTR gene or pharmaceuticals that enhance CFTR (VX809) were locally injected into the gastrocnemius or femoris quadricep to rescue age-related skeletal muscle defects in mice. mRNA levels of CFTR in human vastus lateralis exhibited significantly negative correlations with age (r = -0.87 in males and -0.62 in females, p < 0.05). Gastrocnemius mRNA level of CFTR decreased by 77.7 ± 4.6% in 29-month-old wild-type mice compared to the 4-month-old. At 18-month-old, DF508 mice showed significantly reduced lean mass (by 35.6%), lower specific twitch force of the gastrocnemius (by 46.2%), decrease in fast/slow-twitch muscle isoform ratio as well as downregulation of myogenic (e.g., MYOD and MYOG) or autophagy/mitophagy (e.g., LC3-β) genes, compared to age-matched wild-types. Post-injury gastrocnemius regeneration was found impaired in DF508 mice. Myoblast cultures from DF508 mice showed defective myogenic differentiation, which was reversed by overexpressing LC3-β. In aged (> 15-month-old) mice, overexpressing CFTR or VX809 restored the expression of autophagy or myogenic genes, increased mitochondrial LC3-β level and improved skeletal muscle mass and function. Age-related reduction in skeletal muscle expression of CFTR impairs autophagy and myogenesis, exacerbating skeletal muscle aging. Enhancing CFTR might be a potential treatment strategy for age-related skeletal muscle disorders.

Editorial: Induced pluripotent stem cells (iPSCs) for skeletal muscle diseases

Editorial: Induced pluripotent stem cells (iPSCs) for skeletal muscle diseases

Tumor Lesion Uptake of [177Lu]Lu-DOTA-Rituximab in Skeletal and Splenic Disease in Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, and a sizable fraction of the DLBCL patients presents with advanced, relapsed, and refractory disease, demonstrating poor response to standard chemotherapy regimens. Radioimmunotherapy (RIT) has shown to be clinically effective in refractory DLBCL. We present the case of a patient with DLBCL with [18F]FDG-avid widespread skeletal as well as splenic involvement as poor prognostic extranodal disease on FDG PET/CT. RIT based on [177Lu]Lu-DOTA-rituximab was explored to study the biodistribution and dosimetry of [177Lu]Lu-DOTA-rituximab in CD20-positive lymphoma. An exceptionally high tracer concentration in skeletal and splenic disease was observed, supporting its potential RIT application in relapsed and refractory DLBCL patients in the future.

NEAT1 regulates BMSCs aging through disruption of FGF2 nuclear transport

BackgroundThe aging of bone marrow mesenchymal stem cells (BMSCs) impairs bone tissue regeneration, contributing to skeletal disorders. LncRNA NEAT1 is considered as a proliferative inhibitory role during cellular senescence, but the relevant mechanisms remain insufficient. This study aims to elucidate how NEAT1 regulates mitotic proteins during BMSCs aging.MethodsBMSCs were isolated from alveolar bone of human volunteers aged 26–33 (young) and 66–78 (aged). NEAT1 expression and distribution changes during aging process were observed using fluorescence in situ hybridization (FISH) in young (3 months) and aged (18 months) mice or human BMSCs. Subsequent RNA pulldown and proteomic analyses, along with single-cell analysis, immunofluorescence, RNA immunoprecipitation (RIP), and co-immunoprecipitation (Co-IP), were conducted to investigate that NEAT1 impairs the nuclear transport of mitotic FGF2 and contributes to BMSCs aging.ResultsWe reveal that NEAT1 undergoes significant upregulated and shifts from nucleus to cytoplasm in bone marrow and BMSCs during aging process. In which, the expression correlates with nuclear DNA content during karyokinesis, suggesting a link to mitogenic factor. Within NEAT1 knockdown, hallmarks of cellular aging, including senescence-associated secretory phenotype (SASP), p16, and p21, were significantly downregulated. RNA pulldown and proteomic analyses further identify NEAT1 involved in osteoblast differentiation, mitotic cell cycle, and ribosome biogenesis, highlighting its role in maintaining BMSCs differentiation and proliferation. Notably, as an essential growth factor of BMSCs, Fibroblast Growth Factor 2 (FGF2) directly abundant binds to NEAT1 and the sites enriched with nuclear localization motifs. Importantly, NEAT1 decreased the interaction between FGF2 and Karyopherin Subunit Beta 1 (KPNB1), influencing the nuclear transport of mitogenic FGF2.ConclusionsOur findings position NEAT1 as a critical regulator of mitogenic protein networks that govern BMSC aging. Targeting NEAT1 might offer novel therapeutic strategies to rejuvenate aged BMSCs.

Implementation of Parenteral Nutrition Formulations with Increased Calcium and Phosphate Concentrations and Its Impact on Metabolic Bone Disease in Preterm Infants: A Retrospective Single-Centre Study

Background: Metabolic Bone Disease of Prematurity (MBDP) is common in extremely preterm infants (≤28 weeks gestation). Parenteral nutrition (PN) with higher calcium (Ca) and phosphorus (P) concentration started soon after birth may improve bone health in preterm infants. We compared the effect of two standard PN formulations on the incidence of MBDP and explored the predictive ability of biochemical markers for diagnosing MBDP. Methods: This retrospective study included eligible preterm infants ≤28 weeks gestation. Infants in group 1 (January 2016–December 2017) received PN 1 formulation with lower Ca (1.6 mmol/kg/day) and P concentration (1.4 mmol/kg/day). Infants in group 2 (June 2018–May 2020) received PN 2 formulation with higher Ca (2.3 mmol/kg/day) and P concentration (1.8 mmol/kg/day). We reviewed the biochemical and radiological investigations performed for diagnosing MBDP. Results: The incidence of MBDP reduced from 82.8% (77/93) in group 1 to 47.3% (27/57) in group 2. Grade 2–3 MBDP reduced significantly from 14% in group 1 to none in group 2 (p &lt; 0.01). Serum phosphate &lt;1.5 mmol/L had a sensitivity of 79% and specificity of 77%, and alkaline phosphatase &gt;500 U/L showed a sensitivity of 72% and specificity of 71% for diagnosing radiological MBDP. There was no increase in hypercalcemia, hypophosphatemia or nephrocalcinosis from PN 2 formulation. Conclusions: A higher Ca and P concentration in PN reduced MBDP and eliminated grade 2–3 MBDP in our cohort without an increase in adverse events. Low serum phosphate and high serum alkaline phosphatase were the best predictors for diagnosing MBDP.

Kat7 accelerates osteoarthritis disease progression through the TLR4/NF-κB signaling pathway.

Osteoarthritis (OA) is a common degenerative bone and joint disease with an unclear pathogenesis. Our study identified that the histone acetyltransferase encoded by Kat7 is upregulated in the affected articular cartilage of OA patients and in a mice model of medial meniscal instability-induced OA. Chondrocyte-specific knockdown of Kat7 expression exhibited a protective effect on articular cartilage integrity. In vitro experiments demonstrated that KAT7 promotes cartilage catabolism, inhibits cartilage anabolism, and induces chondrocyte senescence and apoptosis. Conversely, knocking down Kat7 was shown to protect chondrocyte function. Corresponding in vivo results indicated that silencing Kat7 effectively enhances cartilage anabolism, prevents articular cartilage damage, and significantly slows OA progression. Mechanistically, KAT7 activates the TLR4/NF-κB signaling pathway, and inhibition of this pathway reverses the catabolic effects and restores anabolic activity in the presence of Kat7 overexpression. Collectively, these findings confirm the critical role of KAT7 in the pathogenesis of OA and suggest that Kat7 represents a potential therapeutic target for OA treatment. KEY MESSAGES: There is a lack of clinically effective drugs for the treatment of osteoarthritis (OA). Kat7 plays a key role in the development of OA. Knocking down Kat7 expression can alleviate the progression of OA. Kat7 accelerates the progression of OA by activating the TLR4/NF-KB signaling pathway.

The Impact of Traditional Chinese Medicines on Osteoclastogenesis through NF-κB Signaling Pathway: A Review

Osteoclasts are specialized cells responsible for bone resorption, which plays a crucial role in the dynamic processes of bone remodeling and maintenance. Osteolytic skeletal disorders, such as osteoporosis, arise from an imbalance between the activities of osteoclasts and osteoblasts. The regulatory mechanisms underlying osteoclast differentiation, known as osteoclastogenesis, are governed by the receptor activator of nuclear factor kappa-B ligand (RANKL)/receptor activator of NF-κB (RANK)/osteoprotegerin (OPG) signaling system. In this system, the RANK, a type 1 transmembrane protein, acts as a central regulator of osteoclastogenesis through various signaling pathways. This review seeks to explore the influence of Traditional Chinese Medicines (TCM) on osteoclastogenesis, focusing on the NF-κB signaling pathway. This study aims to offer valuable insights into potential therapeutic strategies for managing osteolytic skeletal disorders by investigating the interaction between TCM and the regulatory mechanisms that control osteoclast function. A comprehensive literature review was conducted, concentrating on studies that examine the effects of TCM on osteoclastogenesis and the NF-κB signaling pathway. Databases such as PubMed, Web of Science, and Google Scholar were searched for peer-reviewed articles, reviews, and clinical studies. The inclusion criteria focused on studies addressing the impact of TCM on osteoclast function and the associated molecular mechanisms, especially those involving the RANKL/RANK/OPG system and the NF-κB pathway. The review identified several TCM compounds with regulatory effects on osteoclastogenesis. These compounds were found to modulate the NF-κB pathway, influencing osteoclast differentiation and activity. Key findings highlighted the discovery of specific TCM herbs and their active ingredients that can inhibit osteoclast formation and function, promoting bone health. The mechanisms of action often involved suppressing RANKL-induced NF-κB activation, a crucial process for osteoclast differentiation and bone resorption. This review underscores the potential of TCMs as therapeutic agents for osteolytic skeletal disorders through their modulation of the NF-κB signaling pathway. The findings suggest that TCM may significantly regulate osteoclastogenesis, offering new avenues for developing treatments for conditions like osteoporosis. However, further research and clinical trials are necessary to fully elucidate the therapeutic potential of TCM and translate these findings into clinical practice.

Unraveling the Role of RSPRY1 in TGF-β Pathway Dysregulation: Insights into the Pathogenesis of Spondyloepimetaphyseal Dysplasia

Skeletal dysplasias, characterized by bone, cartilage, and connective tissue abnormalities, often arise due to disruptions in extracellular matrix (ECM) dynamics and growth factor-dependent signaling pathways. RSPRY1, a secreted protein with RING and SPRY domains, has been implicated in bone development, yet its exact role remains to be determined. RSPRY1 gene mutations are associated with spondyloepimetaphyseal dysplasia (SEMD), a rare skeletal disorder characterized by severe epiphyseal and metaphyseal deformities. This study aimed to determine the molecular and cellular mechanisms by which RSPRY1 deficiency affects skeletal homeostasis. Transcriptome analysis of fibroblasts from patients with homozygous RSPRY1 mutations showed there was significant enrichment of transforming growth factor beta (TGF-β) signaling and ECM-related pathways. Functional wound healing assays showed that RSPRY1 knockout fibroblasts exhibited enhanced motility, a phenotype that was abrogated in RSPRY1 + SMAD3 double knockout fibroblasts, highlighting the SMAD3-dependence of RSPRY1′s effects. The observed limited response to exogenous TGF-β in RSPRY1-deficient cells indicated that there was constitutive pathway activation. These findings show that RSPRY1 is a critical regulator of TGF-β signaling in ECM dynamics and cell motility, contributing to the pathophysiology of SEMD. An improvement in our understanding of the molecular roles of RSPRY1 might yield novel therapeutic strategies that target TGF-β signaling in patients with SEMD and other skeletal dysplasias.

The Presence of the Endocannabinoid System in an In Vitro Model of Gorham-Stout Disease and Its Possible Role in the Pathogenesis

Gorham-Stout syndrome (GSD), also known as disappearing bone disease, is an extremely rare bone disorder, characterized by a huge bone loss, which is followed by a lack of new matrix deposition and an excessive proliferation of both blood vessels and lymphatics. Unfortunately, the biological causes of GSD are still unknown. Recent studies that have tried to understand the etiopathogenesis of GSD have been principally focused on the vascular and osteoclastogenic aspects, not considering the possibility of a lack of osteoblast function. Nowadays, a diagnosis is still difficult, and is often made by exclusion of the presence of other pathologies, as well as on radiological evidence, and finally confirmed by histological examination. Treatment also remains a critical issue for clinicians today, who mostly try to control the progression of the disease. Over the last two decades, clear evidence has emerged that the endocannabinoid system plays an important role in bone metabolism, leading scientists to hypothesize that it could be involved in physiological and pathological bone processes. In this work, we analyzed the presence of the ES in a primary cell line of human mesenchymal stem cells derived from a GSD patient for the first time, to understand if and how this complex network may play a role in the pathogenesis of the syndrome. Our preliminary results demonstrated that the ES is also present in the pathological tissue. Moreover, the qRT-PCR analysis showed an altered expression of the different ES components (i.e., CNR1, CNR2, TRPV1, and GPR55). We observed an upregulation of CNR1 and TRPV1 expression, while the opposite trend was noticed for CNR2 and GPR55 expression. Thus, these results could lead us to speculate that possible deregulation of the ES may play an important role in the lack of bone regeneration in GSD patients. However, further studies will be necessary to confirm the role of the ES in the progression of GSD and understand whether the natural components of Cannabis Sativa could play a therapeutic role in the treatment of the disease.

How Effective is Low-dose Radiotherapy (LD-RT) for Heberden's Osteoarthritis? An Analysis of the Current Literature.

Low-dose radiotherapy is an established treatment option for non-malignant skeletal disorders. It is used in the treatment of Heberden's osteoarthritis (HA), but the evidence of efficacy does not seem to be certain. This paper reviews current literature for scientific evidence of efficacy in the treatment of HA.The PubMed and Cochrane Library databases were searched for relevant publications.9 publications were identified that published data from 7 studies. Only one study was randomised, placebo-controlled and double-blinded. None of the studies exclusively investigated HA. The studies were all inhomogenous with regard to inclusion criteria, follow-up criteria, radiation mode and interpretation or treatment success. In the RCT, no difference was found between the verum and control groups.The study situation is currently weak. The researched publications are not sufficiently focused on the collective of Heberden's osteoarthritis and are generally too inhomogenous with regard to the criteria applied. Future targeted studies are therefore required to prove efficacy.