Calcified Tissue International最新文献

Type H vessels are sensitive markers of bone mass. Platelet-derived growth factor-BB (PDGF-BB) secreted by preosteoclast was linked with type H vessel generation. Osteocytes (OCY) have been reported to modulate bone metabolism through neuronal induction and active molecules. This study aimed to characterize effect of osteocyte-derived neuropeptide Y (NPY) on ovariectomy (OVX)-induced bone loss in mice and explore the underlying mechanism. Monocytes/macrophages (Mo) were isolated and induced into preosteoclast. Small interfering RNAs were used to knockdown NPY expression in OCY. The culture medium was harvested. Preosteoclast proliferation and PDGF-BB expression were measured by CCK8 analysis and ELISA respectively. Angiogenesis-related experiments were conducted to evaluate the effects of NPY and PDGF-BB on angiogenesis. Western blotting clarified PI3K/Akt pathway involvement in NPY-mediated angiogenesis. In vivo, OVX mice received cultured medium from OCY with NPY knockdown, NPY or vehicle through bone marrow cavity injection. After 2 months, bone samples were collected for µCT and immunofluorescent analysis. Serum OCN, PDGF-BB and VEGF concentrations were assessed by ELISA. It was found that osteocyte-derived NPY inhibits preosteoclast proliferation and PDGF-BB secretion. Culture medium from NPY-stimulated preosteoclasts suppressed migration and tube formation of human microvascular endothelial cells and this effect was reversed following PDGF-BB treatment. NPY negatively regulates preosteoclast PDGF-BB-induced angiogenesis through PI3K/Akt signaling. Importantly, osteocyte NPY exerted detrimental effects on type H vessel formation and aggravated bone loss in OVX mice. Our study identifies a new mechanism by which osteocyte-derived NPY accelerates OVX-induced bone mass loss via inhibiting PDGF-BB secretion and type H vessel formation.

Hormone replacement therapy in women usually focuses on estrogen and progesterone replacement. But also androgens decrease with age in women. Decrease of estrogen or androgens levels are associated with bone loss, while steroid hormone therapy often leads to negative side effects. A possible solution could be the use of selective receptor modulators (SRMs). Here, a combined treatment with a selective estrogen receptor modulator (raloxifene, RAL) and a selective androgen receptor modulator (ostarine, OST) was investigated in ovariectomized rats. The study was performed using 3-month-old female Sprague-Dawley rats. Fifteen control rats were not ovariectomized (NON-OVX). Sixty rats were ovariectomized and divided into 4 groups (n = 15/group): (1) untreated rats (OVX), (2) rats receiving OST (0.55 ± 0.08 mg/kg body weight [BW]), (3) rats receiving RAL (11.07 ± 1.77 mg/kg BW), (4) rats treated with OST and RAL. The compounds were administered orally as osteoporosis prophylaxis immediately after ovariectomy for up to 13 weeks. Thereafter, the lumbar vertebrae and femora were analyzed.OST + RAL treatment showed a favorable effect on structural and biomechanical bone parameters, demonstrating some advantages over RAL alone. RAL confirmed its antiresorptive effect on bone tissue without causing negative systemic effects. OST alone was less effective in protecting bone tissue. It increased osteoblast number, serum phosphorus, bone magnesium, and inner organ and uterus weight. The adverse effect of OST on bone magnesium level was attenuated when combined with RAL. Conversely, the combined treatment increased serum phosphorus and luteinizing hormone levels, decreased serum magnesium and calcium, and did not attenuate the organ and uterus weight increase observed after OST, raising safety concerns. These findings highlight the need for cautious evaluation of combination therapies and suggest that there is a need for alternative compounds with improved safety profiles for future osteoporosis treatments.

It was widely acknowledged that patients with anorexia nervosa (AN) present a decrease in areal bone mineral density (aBMD), but the effect on bone microarchitecture and other parameters associated with fracture risk have been less well investigated. The two aims of this study were to (i) compare aBMD at various bone sites as determined by DXA, as well as trabecular and cortical volumetric BMD (vBMD) at femoral regions using 3D-Shaper® software, in young women with AN and normal-weight controls (CON) and (ii) determine the factors potentially associated with aBMD and vBMD. Three hundred young women from 18 to 35 years old were enrolled in this study: 209 patients with AN and 91 age-matched normal-weight controls. aBMD was determined with DXA and vBMD by 3D-Shaper® software. Compared with controls, patients with AN presented significantly lower aBMD at all bone sites, but the difference was greater at hip and lumbar spine compared with radius. In whole proximal femur and all femoral compartments, vBMD was also lower in patients, but the difference between groups was greater for cortical vBMD compared with trabecular vBMD. Cortical thickness was also altered but to a lower extent. The bone deterioration induced a decrease in bone structural parameters. In the patients, the independent variables for determining aBMD and vBMD were principally minimal disease-related BMI, menstrual disorder status and duration of amenorrhea. This study confirmed not only that young women with AN present lower aBMD across the skeleton, but it also showed for the first time a concomitant deterioration in trabecular and cortical vBMD and cortical thickness as measured by 3D-Shaper®, leading to a decrease in bone structural parameters. In future, it will be interesting to determine whether 3D-Shaper® parameters are more sensitive than aBMD for monitoring skeletal changes due to weight variations or during therapeutic interventions. It will also be relevant to assess whether these new bone parameters are more predictive of fracture risk than aBMD in these patients.

Proton-pump inhibitors (PPI) are widely used among older adults and PPI intake has been associated with increased fracture risk. However, their association with bone microarchitecture and strength remains unclear as prior clinical PPI studies were restricted to lower-resolution bone imaging techniques such as DXA. Using high-resolution peripheral computed tomography (HR-pQCT), we prospectively investigated whether long-term PPI use was associated with changes in volumetric bone mineral densities, bone microarchitecture, and strength in older patients. 189 patients aged ≥ 60 years (n = 24 persistent PPI users [p-PPI user], and n = 165 non-PPI users), enrolled as part of a 2-year vitamin D RCT, underwent HR-pQCT scanning of the tibia and radius at 0 and 2 years. Bone volumetric density (vBMD), microarchitectural and strength parameters were computed and adjusted linear regression models without and with adjustments, including age, sex, BMI, and treatment groups, were employed to compare changes between p-PPI users and non-PPI users. At baseline, both groups were comparable with respect to age, vBMDs, bone microarchitecture, and sex. During follow-up, p-PPI users lost significantly more distal tibial total volumetric BMD (ΔTt.BMD: - 8.58 vs. - 2.45 mg/cm³, p = 0.012) and cortical volumetric BMD (ΔCt.BMD, - 28.96 vs. -14.07 mg/cm³, p = 0.005), and showed a significantly greater loss in tibial bone strength (Δstiffness - 4848.1 vs. 20.7 N/mm, p = 0.029; Δfailure load - 204.5 vs. 16.7 N, p = 0.026) than non-PPI users. At the radius, p-PPI users showed over the 2 years significantly greater increases in cortical porosity and intracortical pore diameter than non-PPI users (ΔCt.Po, p = 0.005; ΔCt.PoDm, p = 0.009). Long-term PPI intake was associated with a significant decline in cortical microarchitecture at the radius and with a significant deterioration of volumetric bone mineral density and strength at the tibia in older patients.

Purpose: To examine the association between birth characteristics and bone mineral density (BMD) and bone mineral content (BMC) in young adults.

Methods: Data from 3,174 participants aged 20-54 years from the 3rd (2006-2008) and 4th (2017-2019) HUNT Study surveys were linked to the Medical Birth Registry of Norway. BMD and BMC of femoral neck were measured using dual-energy X-ray absorptiometry (DXA). Linear regression estimated mean differences in BMD and BMC by birth characteristics, adjusting for sex, birth year, age at scan, maternal age, and maternal morbidity.

Results:  At bone densitometry, participants had a mean age of 34.2 years, with mean BMD of 0.971 g/cm², and mean BMC of 5.398 g, at the femoral neck. A standard deviation (SD) increase in ponderal index (PI) and birth weight was associated with higher BMD of 0.024 g/cm² (95% CI 0.006, 0.042) and 0.015 g/cm² (95% CI 0.009, 0.022). Individuals born large for gestational age (LGA) had 0.023 g/cm² (95% CI 0.007, 0.039) higher BMD than those born appropriate for gestational age (AGA), while low birth weight (LBW)(< 2.5 kg) was associated with - 0.028 g/cm² (95% CI - 0.053, - 0.003) lower BMD. For BMC, an SD increase in PI and birth weight was associated with 0.171 g (95% CI 0.048, 0.293) and 0.146 g (95% CI 0.112, 0.181) higher BMC, respectively. LGA had 0.206 g (95% CI 0.090, 0.313) higher BMC, while LBW was associated with - 0.298 g (95% CI - 0.469, - 0.127) lower BMC.

Conclusion: Higher ponderal index, birth weight, and gestational age were positively associated with BMD and BMC in young adulthood.

Genome-wide association studies have identified multiple loci associated with bone mineral density, a major determinant of osteoporotic fracture risk. At one such locus, genetic, bioinformatic, and zebrafish knockout data strongly prioritize membrane palmitoylated protein 7 (MPP7) as a candidate gene, although its precise role in bone biology remains poorly defined. MPP7 encodes a member of the p55 Stardust family of membrane-associated guanylate kinase proteins, which are key regulators of epithelial cell polarity and junctional organization. Here, we investigated the functional role of MPP7 in bone biology. We found that MPP7 expression was significantly reduced-by approximately twofold-in bone tissue from osteoporotic patients compared with osteoarthritic patients and non-osteoporotic controls. Furthermore, we generated a CRISPR/Cas9-mediated MPP7 knockout in the human osteosarcoma HOS cell line and demonstrated that MPP7 deletion impairs osteogenic differentiation and completely abrogates mineralization through downregulation of ALPL expression. Knockout cells also displayed altered morphology, suggesting that MPP7 influences osteoblast function via effects on cell polarity and adhesion. Collectively, our findings, together with zebrafish genetic evidence, indicate that MPP7 plays a critical role in osteoblast differentiation and mineralization and may contribute to osteoporosis susceptibility in humans.

Chronic hepatitis C (CHC) is a risk factor for hepatic osteodystrophy, increasing osteoporosis and fracture risks. While historical pegylated interferon/ribavirin (PEG-IFN/RBV) showed variable bone effects, the newer direct-acting antivirals' (DAAs) impact is less clear. This study compared these antiviral strategies' effects on bone metabolism in CHC patients through two separate analyses. First, we conducted a retrospective analysis of a prospectively collected observational cohort (n = 73) to assess longitudinal bone mineral density (BMD) and bone turnover marker (BTM) changes following PEG-IFN/RBV or DAA therapies. Second, to explore mechanisms, we analyzed two independent, publicly available peripheral blood mononuclear cell (PBMC) transcriptomic cohorts from CHC patients treated with PEG-IFN/RBV (GSE7123, n = 69) or an IFN-free DAA regimen (GSE51699, n = 8). Clinically, PEG-IFN/RBV induced a temporary lumbar spine BMD increase, then a post-treatment decline, and modulated BTMs. DAAs showed minimal BMD/BTM effects. PBMC transcriptomics revealed PEG-IFN/RBV responders showed downregulation of osteoclast precursor (OCP)-related gene sets and concurrent upregulation of osteoblast-related gene sets. DAAs had a minimal impact on these PBMC pathways. These findings demonstrate distinct effects of PEG-IFN/RBV and DAA therapies. PEG-IFN/RBV significantly modulates PBMC gene expression related to bone remodeling, potentially contributing to the complex clinical BMD changes, while DAAs appear largely bone-neutral. This highlights treatment-specific osteoporosis risk and surveillance needs in CHC survivors.

Tissue engineering creates possibilities for promoting bone regeneration, which can culminate in an ideal therapy for treating bone defects. Considering its tools, especially exosomes (Exos), inferring its efficiency is fundamental for future clinical protocols. Therefore, this research aimed to analyze, through a systematic review, the effectiveness of Exos therapy for regenerating bone. The study followed the PRISMA, and an electronic search for literature was performed until January 2024 to answer the PICO question: Would exosome therapy be effective for bone regeneration? Bone regeneration and cellular and molecular mechanisms were included in primary and secondary outcomes, respectively. The dosage, route of administration, and source cells have also been reported. The risk of bias was investigated according to the criteria of SYRCLE's RoB tool. The meta-analysis was executed using the standardized mean difference for bone mineral density (BMD) and volume ratio bone/whole bone (BV/TV) for cranial bone defects. A total of 3718 were examined, and after applying the eligibility criteria and excluding duplicates, 91 articles were included in the results. All studies demonstrated that Exos were effective in promoting regeneration of bone defects, being superior to the control groups established by each study included in this review, in most cases. The meta-analysis proved the superiority of Exos when BMD and BV/TV were analyzed. An increase in the levels of Runx2, ALP, OCN, OPN, CD31, COL-1, and VEGF, and presence of osteoblasts, M2-type macrophages, and endothelial cells, indicating osteogenic and angiogenic molecular and cellular mechanisms. The mesenchymal stem cells are the most commonly used origin cells. Exos dosage was varied, associated with scaffolds or hydrogels for application in bone defects. The risk of bias identified high scientific evidence for most domains. The Exos therapy is effective for bone regeneration and shows promise for this purpose.