Calcified Tissue International最新文献

Rheumatoid arthritis (RA) is associated with systemic bone loss and thus an established risk factor for osteoporosis. Janus kinase inhibitors (JAKi) have shown osteo-protective effects. However, clinical data on the effects of baricitinib on bone mineral density (BMD) remain limited. Therefore, we investigated the effects of a 1-year treatment with baricitinib on BMD in RA patients. Patients with active RA beginning treatment with baricitinib were included. BMD was measured at the lumbar spine and femoral neck using Dual-Energy X-Ray Absorptiometry (DXA). Disease activity was assessed using DAS28-CRP and cDAI. The primary endpoint was the change in BMD after 12 months. Secondary endpoints evaluated changes in disease activity, prednisolone dose and alkaline phosphatase (AP) levels and its relation to BMD. A total of 46 RA patients were recruited, of whom 26 completed the study. Overall, BMD remained stable. Non-responders to baricitinib (based on DAS28-CRP) showed a significant decline in spine BMD (- 2.12%, p = 0.039), while responders showed stable BMD. The between-group difference in spine BMD (p = 0.008) and T-score (p = 0.012) was significant. Demographic and clinical characteristics did not differ significantly between groups. Disease activity (DAS28-CRP: p = 0.003; cDAI: p = 0.007), prednisolone dose (p = 0.006), and AP levels (p = 0.03) all improved significantly. Under baricitinib, BMD loss appeared stabilized in RA patients. Non-responders to baricitinib experienced a significant loss of BMD with a significant difference to responders raising the question if seen effects are achieved by controlling disease activity or if there is an additional explicit JAKi effect on bone metabolism. Trial registration number: DRKS00020780, date: 13.3.2020.

The balance between adipogenesis and osteogenesis in mesenchymal stem cells (MSCs) is pivotal for the maintenance of bone homeostasis. However, the genes responsible for regulating this balance are still not fully understood. This investigation sought to explore and identify novel genes that influence MSC differentiation into adipogenic and osteogenic lineages, thereby enhancing bone formation. Four datasets from the Gene Expression Omnibus (GEO) database were utilized: three focused on osteogenic differentiation (GSE73087, GSE18043, GSE114117), and one on adipogenic differentiation (GSE37836). Differentially expressed genes (DEGs) during both osteogenic and adipogenic differentiation processes were analyzed using the limma R package. A sum of 471 common differentially expressed genes (CDEGs) were found in MSC osteogenesis, comprising 240 elevated and 231 reduced genes. Similarly, in MSCs adipogenesis, 204 elevated genes and 459 reduced genes were identified. Fourteen hub genes were found to overlap between the CDEGs associated with MSC osteogenesis and DEGs linked to adipogenic differentiation. Notably, the expression of aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) was elevated during osteogenesis but reduced during adipogenesis. Overexpression of ARNT2 enhanced the expression of osteogenic markers in MSCs, while its suppression led to a decrease in osteogenic marker expression. Protein-protein interaction network analysis revealed that ARNT2 interacts with Hypoxia inducible factor 1 subunit alpha (HIF1A), B-cell lymphoma 6 (BCL6), Ubiquitin-specific-processing protease 7 (USP7), and Single-minded homolog 2 (SIM2), which are implicated in the regulation of MSCs osteogenesis. In summary, fourteen hub genes were identified as potential regulators in the osteo-adipogenic differentiation of MSCs. Among them, ARNT2 was confirmed to promote osteogenesis in MSCs and exhibited potential as a therapeutic target for bone-related diseases.

Poor adherence to oral bisphosphonate therapy remains a major challenge in the treatment of osteoporosis, substantially reducing therapeutic efficacy. While reminder interventions have been proposed as a method to enhance adherence, evidence remains limited. This study aimed to evaluate the impact of written and verbal reminders on medication adherence compared to standard patient care over a 12-month period in a real-world clinical setting. In this randomized controlled study, 180 postmenopausal women diagnosed with osteoporosis were assigned to one of three groups: standard care (control), written reminder, or verbal reminder. Interventions were administered at five standardized time points. Adherence was defined as intake of ≥80% of prescribed weekly doses (≥42 out of 52 doses) and a ≥35% reduction in serum C-terminal telopeptide of type I collagen (CTX) levels from baseline to 12 months. No significant differences in adherence rates were observed between groups: 53.2% in the control group, 52.0% in the written reminder group, and 52.7% in the verbal reminder group (χ² = 0.014; p = 0.993). Changes in bone mineral density and serum CTX levels were also comparable across groups. The implementation of standardized written or verbal reminder strategy did not result in a statistically significant improvement in adherence to oral bisphosphonate therapy. Further studies are needed to investigate the reasons for low adherence to treatment.

Intermittent administration of parathyroid hormone (PTH) produces potent anabolic effects on bone. These anabolic effects appear to be mediated by activation of the Gs-cyclic AMP system initiated by the PTH1 receptor (PTHR1) in osteoblast lineage cells. Gs-mediated cyclic AMP production can be inhibited by activation of Gi signaling, and we have previously demonstrated that Gi signaling in osteoblasts suppresses bone formation and thereby plays a prominent role in the bone loss associated with aging in female mice. It is not clear whether this increased Gi signaling with aging dampens the anabolic response to intermittent PTH (iPTH) administration. To address this possibility, we determined the effect of inducible blockade of Gi signaling in osteoblasts on the anabolic response to PTH in 4-month-old female mice. Blockade of Gi signaling was achieved by tetracycline-regulated expression of pertussis toxin (PTX) driven by a Col1(2.3) promoter. We found that the expression of PTX potentiated the anabolic effect of iPTH on the trabecular bone, both at the distal femur and L4 lumbar vertebra. In addition, the ability of PTH to promote cortical bone thickness and strength was evident only in mice expressing PTX. These novel results demonstrate that endogenous Gi signaling in osteoblasts limits the anabolic action of iPTH on the skeleton of adult female mice. Strategies that suppress osteoblast Gi signaling could provide an effective adjunct to iPTH therapy in the treatment of postmenopausal osteoporosis.

The systemic administration of cisplatin has been shown to substantially reduce skeletal muscle mass. This is a serious concern, as muscle loss is correlated with increased mortality in patients with cancer. Cisplatin also contributes to cognitive decline, but the exact mechanism thereof remains unclear. In this study, we focused on fibronectin type III domain-containing 5 (Fndc5), a gene that produces irisin, a myokine that is important for brain health. Male C57BL/6J mice (8-9 weeks old) were injected with cisplatin or saline for 4 consecutive days. Twenty-four h after final injection of cisplatin, quadriceps muscles were isolated. C2C12 myotubes were treated with cisplatin with/without AICAR. In male C57BL/6J mice treated with cisplatin, a reduced expression of the key regulator PGC-1α was observed, along with reduced levels of Fndc5/irisin mRNA and protein in the mice quadriceps muscles. Similar findings were seen in cisplatin-treated C2C12 myotube cells, where the activation of PGC-1α with AICAR partially offset these effects. These results suggest that cisplatin inhibits the synthesis of Fndc5/irisin and may contribute to the metabolic changes and cognitive decline observed in patients with cancer who receive this treatment.

This study aims to investigate the heterogeneity and function of bone marrow T cells in postmenopausal osteoporosis (PMOP). Single-cell transcriptome sequencing was employed to cluster T cells from the femoral bone marrow of mice with PMOP. A subgroup of T cell closely related to postmenopausal osteoporosis was identified. This T-cell subgroup, which highly expresses CD8a, GZMK, CD6, and fewer expresses GZMA, was defined as CD8a + GZMK + T cells. Flow cytometry and analysis of mice femur samples showed a negative correlation between bone loss and the CD8a + GZMK + T-cell population. Tartrate-resistant acid phosphatase (TRAP) staining and immunofluorescence staining showed a marked reduction in both quantity and fusion of osteoclasts in primary bone marrow macrophages (BMMs) co-cultured with CD8a + GZMK + T cells. qPCR analysis revealed lower expression of genes-NFATC1, CTSK, TRAP, MMP9, and FOS- related to osteoclastogenesis. Similar inhibitory effects on osteoclastogenesis were observed in vitro with treatment using recombinant Granzyme K (GzmK), with effects intensifying as the GzmK concentration increased. RNA sequencing and Western blot analyses revealed significant suppression of the MAPK signaling pathway. The MAPK agonist could partially counteract the inhibitory effects of GzmK on osteoclastogenesis. This study elucidated the heterogeneity of T cells during the pathological process of PMOP. We identified and characterized a T-cell subset, CD8a + GZMK + T cells, which secrete GzmK and inhibit osteoclastogenesis via the P38-MAPK pathway. These findings provide new insights into the role of T cells in the pathology of PMOP and suggest potential therapeutic targets for its treatment.

The present study aimed to determine the influence of different degrees of energy restriction (ER) on the bones in young female rats. Forty female Sprague-Dawley rats (n = 40; age, 6 weeks) were randomly divided into the following five experimental groups after a 1-week acclimatization period: 0% ER, 10% ER, 20% ER, 30% ER, and 40% ER groups. The experimental period was 10.5 weeks. Statistical analysis was conducted using one-way analysis of variance, Tukey's post hoc comparison tests, and simple linear regression analysis. The body weight and fat weight showed significantly lower values above 20% ER. The bone mineral content and bone mineral density of the tibia in the 30% ER group were significantly lower than those in the 10% and 20% ER groups, and those in the 40% ER group was significantly lower than those in the 0%, 10%, and 20% ER groups. The trabecular thickness, cortical bone volume, and cortical total volume in the 40% ER group were significantly lower than those in the 0% ER group. The serum levels of parathyroid hormone, bone-specific alkaline phosphatase, and tartrate-resistant acid phosphatase significantly increased with increasing degree of ER. However, the serum levels of leptin, carboxylated osteocalcin, and carboxylated osteocalcin / uncarboxylated osteocalcin significantly decreased with increasing degree of ER. Our findings showed that 30% or 40% ER resulted in lower bone mass and 40% ER impaired bone microstructure in young female rats. However, 10% or 20% ER did not affect these parameters.

Type 1 diabetes (T1D) and T2D are associated with skeletal fragility, contributing to increased fracture risk. Whereas decreased bone mineral density (BMD) is common in T1D, individuals with T2D tend to have normal or elevated BMD. These differences are incompletely understood but may stem from distinct mechanisms. Previously, we showed that obese male C57BL/6 mice (7-month-old) with T2D exhibit poor bone quality and accelerated osteocyte senescence with a unique senescence-associated secretory phenotype (SASP). We hypothesized that, similar to T2D, senescent osteocytes and additional senescent bone-resident cells (e.g., immune cells) accumulate in T1D. Consistent with previous studies, we studied a juvenile onset (2-month-old) T1D model, where following 8 weeks, male C57BL/6 mice with T1D displayed deteriorated bone microarchitecture, increased cortical porosity, and reduced bone strength. Unexpectedly, osteocytes, myeloid cells, T cells, and B cells in T1D mice showed no significant changes in key senescence/SAPS markers. Therefore, although T1D mice display several aspects of poor bone quality, consistent with juvenile-onset T1D in humans, senescent cells have yet to accumulate at substantial levels in bone at this young age. Future studies should include female mice and test whether senescence requires a later onset of T1D, a longer disease duration, or worse glycemic control.

To investigate the feasibility and accuracy of 100 kV low-voltage quantitative CT (QCT) for bone mineral density (BMD) measurement using the European Spine Phantom and patients. The accuracy and precision of the BMD measurements were assessed using relative measurement error (RME%), coefficient of variation (CV%), root mean square standard deviation (RMS-SD), and root mean square CV (RMS-%CV). Linear regression and Bland‒Altman analyses were used to assess the agreement between 100 and 120 kV QCT-based BMD measurements. The diagnostic performance of 100 kV QCT for osteoporosis was evaluated using receiver operating characteristic curve analysis. For the ESP, the mean BMD values at 100 kV were slightly greater than those at 120 kV, mainly due to small inaccuracies remaining in the BMD calibration process. The RME% values for all vertebrae were -3.31 to 15.00% at 100 kV and -9.34 to 3.06% at 120 kV, falling within ± 10% at 120 kV but within 0‒15% at 100 kV. The CV% and RMS-%CV values decreased as the BMD increased with increasing tube voltage, while the RMS-SD exhibited a decreasing trend. For patients, linear regression and Bland‒Altman analyses revealed good agreement between 120 and 100 kV (R² = 0.987, P < 0.001; mean error, -3.39 mg/cm³; 95% limits of agreement, -16.49 to 9.71 mg/cm³). The 100 kV QCT achieved high accuracy in diagnosing osteoporosis (AUC = 0.992, P < 0.001), with a sensitivity of 99.04% and a specificity of 94.28%. 100 kV low-voltage QCT demonstrated acceptable accuracy and good reproducibility for measuring BMD, opening the possibility of 100 kV low-voltage chest CT obtained for lung cancer screening for opportunistic osteoporosis screening.