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Conotoxins from sea snails as potential bone Remodeling disruptors

Abstract The ocean provides food and shelter to diverse marine species, and it is an exceptional source of potential bioactive natural products with promising medicinal properties. Among these, α-conotoxins from venom sea snails show tremendous potential. Our study characterized the effects of synthetic α-conotoxins, sXm1b and sVc1.1, on bone remodeling. Transcriptomic analysis showed significant modulation of critical biological processes, leading to increased osteoclast activity and decreased osteoblast mineralization. sXm1b and sVc1.1 treatment also promoted genes involved in osteoblast and osteoclast proliferation. Interestingly, sVC1.1 showed higher osteoclast gene modulation and reduced the expression of genes critical for osteoblast development and differentiation. In vitro, functional evaluations demonstrated increased osteoclastogenesis and resorption, along with decreased differentiation and mineralization by osteoblasts. In a 3D ex vivo calvaria culture model, these conotoxins significantly decreased bone area, increased osteoclast number, and modulated the expression of osteoclast- and osteoblast-related genes. The findings highlight the promise of α-conotoxins as modulator of bone remodeling for treating non-genetic bone mass accumulation problems, while also cautioning about potential adverse effects on bone in individuals undergoing conotoxin therapy for pain management.

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ADAM: Automated Digital phenotyping And Morphological texture analysis of bone biopsy images using deep learning

Abstract Histomorphometric analysis of undecalcified bone biopsy images provides quantitative assessment of bone turnover, volume, and mineralization using static and dynamic parameters. Traditionally, quantification has relied on manual annotation and tracing of relevant tissue structures, a process that is time-intensive and subject to inter-operator variability. We developed ADAM, an automated pipeline for digital phenotyping, to quantify tissue and cellular components pertinent to static histomorphometric parameters such as bone and osteoid area, osteoclast and osteoblast count, and bone marrow adipose tissue (BMAT) area. The pipeline allowed rapid generation of delineated tissue and cell maps for up to 20 images in less than a minute. Comparing deep learning-generated annotation pixels with manual annotations, we observed Spearman correlation coefficients of ρ = 0.99 for both mineralized bone and osteoid, and ρ = 0.94 for BMAT. For osteoclast and osteoblast cell counts, which are subject to morphologic heterogeneity, using only brightfield microscopic images and without additional staining, we noted ρ = 0.60 and 0.69, respectively (inter-operator correlation was ρ = 0.62 for osteoclast and 0.84 for osteoblast count). The study also explored the application of Morphological Texture Analysis (MTA), measuring relative pixel patterns that potentially vary with diverse tissue conditions. Notably, MTA from mineralized bone, osteoid, and BMAT showed differentiating potential to identify common pixel characteristics between images labeled as low or high bone turnover based upon the final diagnostic report of the bone biopsy. The AUC-ROC obtained for BMAT MTA features as a classifier for bone turnover, was 0.87, suggesting that computer-extracted features, not discernable to the human eye, hold potential in classifying tissue states. With additional evaluation, ADAM could be potentially integrated into existing clinical routines to improve pathology workflows and contribute to diagnostic insights into bone biopsy evaluation and reporting.

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How neighborhood socioeconomic status, green space, and walkability are associated with risk for fracture among postmenopausal women

Abstract Although most fractures, and about half of hip fractures, occur outdoors among older women, limited research has uncovered neighborhood predictors for fractures among older women. This study assessed the independent associations of neighborhood socioeconomic status, walkability, and green space with incident any and hip fracture among postmenopausal women. The Women’s Health Initiative recruited a national sample of postmenopausal women (50-79 years) across 40 U.S. clinical centers and conducted yearly assessments from 1993 to 2012 (n = 161 808). Women reporting a history of hip fracture or walking limitations were excluded from the analytic sample, yielding a final sample of 157 583 participants. Fracture events were self-reported and adjudicated annually. Walkability was calculated annually using measures of population density, land use mix, and presence/quantity of nearby high-traffic roadways. Neighborhood green space was calculated annually using measures of exposure to trees/vegetation. Neighborhood SES, walkability, and green space were categorized intro tertiles: high, intermediate, and low. The time-varying relationship between neighborhood environmental factors and age at first fracture (any; hip) was examined using extended Cox proportional hazards modeling with adjustment. Neighborhood socioeconomic status (intermediate vs low: hazard ratio = 1.03, 95% Confidence Interval (CI): 1.01-1.05; high vs low, hazard ratio = 1.01, 95% CI: 0.99-1.03) and green space (intermediate vs low, hazard ratio = 1.15, 95% CI: 1.12-1.18; high vs low hazard ratio = 1.18, 95% CI: 1.15-1.21) were associated with increased any incident fractures, while walkability had a mixed association (intermediate vs low hazard ratio = 1.06, 95% CI: 1.04-1.07; high vs low, hazard ratio = 0.97, 95% CI: 0.95-0.98). Neighborhood socioeconomic status, walkability, and green space did not have a relationship with hip fracture after adjustment for important covariates. Results indicate that macroscale neighborhood features did not protect against fractures. Additional research is needed to investigate more granual neighborhood features that might influence injury risk and support physical activity among postmenopausal women.

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Proteomic analysis and effects on osteogenic differentiation of exosomes from patients with ossification of the spinal ligament

Abstract Ossification of the spinal ligament (OSL), including ossification of the posterior longitudinal ligament (OPLL) and ossification of the ligamentum flavum (OLF), is a multifactorial disease that includes genetic predisposition. The association between the rate of ossification in the spinal canal and the severity of myelopathy symptoms is well known, but the degree of progression varies widely among patients. Although many candidate genes and biomarkers have been reported, there are no definitive and quantitative conclusions to date, probably because of low reproducibility due to individual differences. In this study, we focused on exosomes secreted by ossified spinal ligament cells. Exosomes are crucial for intercellular communication during development and progression of disease. In a co-culture study of non-OLF cells with OLF cells, there was increased osteogenic differentiation, including Runx2 and Wnt3a expression, with use of exosome-penetrating filters (1.2 μm) compared to exosome-non-penetrating filters (0.03 μm). Dose-dependent increases in alkaline phosphatase activity and mineral deposition were observed in non-OLF cells treated with OLF-derived exosomes. These results support the hypothesis that OLF-derived exosomes are involved in regulation of osteogenic differentiation. In comparative proteomics analysis, 32 factors were increased and 40 were decreased in OLF-derived exosomes compared to non-OLF-derived exosomes. Molecular network analysis of these 72 factors indicated 10 significant pathways, including the MMP signaling, mTOR signaling, Wnt signaling and VDR-associated pathways. Among the upregulated exosomal membrane proteins in OLF samples, COL IV, FMNL3, mTORC2, and PIP4K showed increased expression with greater ossification, suggesting they may serve as biomarkers of disease activity and therapeutic targets. These factors are involved in the PI3K/Akt/mTOR signaling pathway, and particularly mTOR is known to regulate osteogenic and chondrogenic differentiation. In contrast, FABP5, several KRT family proteins, S100A8, SERPINB3, and TGM, were significantly downregulated in OLF-derived exosomes. These findings provide novel insights into the molecular mechanisms underlying OSL pathogenesis.

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Factors associated with impaired physical functionality in x-linked hypophosphatemia

Abstract X-linked hypophosphatemia (XLH) is a rare inherited disorder characterized by elevated levels of fibroblast growth factor-23 (FGF23), chronic hypophosphatemia, impaired bone mineralization and chronic long-term manifestations. Treatment for XLH has been mainly focused on normalizing its biochemical abnormalities. Despite treatment, patients with XLH often present impaired physical function and decreased quality of life (QoL). We hypothesize that physical functionality and QoL is more strongly associated with chronic pain and decreased muscle mass than persistent biochemical abnormalities or exposure to conventional treatment. We conducted an observational, cross-sectional study with patients with XLH. Clinical records and biochemical parameters were assessed. QoL surveys SF36v.2 and WOMAC were applied. Functional status was measured by a physiatrist and an occupational therapist. Appendicular lean mass (ALM) was measured and compared to age and sex-matched healthy controls. Enthesopathies and osteoarthritis were evaluated. Pain was assessed using the Brief Pain Inventory, the Visual Analog Scale and the Doleur Neuropathique-4 scales. Muscle strength was evaluated by the Quadriceps Muscle isometric Strength (QMS) and physical performance with the 6-minute walk test (6MWT) and the Functional Independence Measure (FIM) scale. A total of 30 patients were included: 21 females; median age of 32 years. All participants had significant functional deficits, chronic pain and reduced QoL. Limitations in daily activities were significantly associated with higher severity of pain, decreased ALM, lower QMS, and less distance in 6MWT (P<.05). Neither FIM scale, phosphate levels, FGF23, nor the lifetime exposure to conventional treatment were associated with these functional variables. In conclusion, impaired physical functionality in patients with XLH was associated with lower muscle mass, lower muscle strength and severe chronic pain. These findings highlight the importance of, in addition to optimizing the biochemical control of the disease, expanding patient care including pain prevention and management as well as comprehensive physical therapy and rehabilitation.

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Most infants with prenatal Osteogenesis Imperfecta diagnosis and poor prognosis survive: experience of a quaternary care OI Center

Abstract Osteogenesis imperfecta (OI) is a genetic condition with improperly or inadequately produced Type I collagen. Manifestations include bowing deformities, fractures, hydrocephalus, respiratory insufficiency and feeding difficulty. Moderate or severe OI is often diagnosed prenatally based on ultrasound findings and genetic testing may be labeled as lethal. Here we present 18 infants with moderate to severely presenting OI who received neonatal care at a single center over a 5 year period, 10 of which were delivered at our institution. All 18 infants survived to neonatal discharge, with seven infants requiring respiratory support and nine infants requiring feeding support at discharge. Through Fisher Exact Test, Mann Whitney U Test and backward elimination regression, we do not observe that lethal or possibly lethal diagnoses prenatally were correlated with medically relevant outcomes such as need for respiratory support at discharge or need for feeding support at discharge. 16/18 individuals are alive, with a minority requiring either respiratory or feeding support. With a multidisciplinary team approach to neonatal care, outcomes may be optimized. Infants formerly diagnosed with lethal OI may survive. Given our findings, and lack of correlation of prenatal assessments with survival and other medical outcomes, we recommend all families be given the option to pursue medical interventions.

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Oncogenic FLT3 internal tandem duplications (ITD) and CD45/PTPRC control osteoclast functions and bone microarchitecture.

Activating internal tandem duplications (ITD) in the juxtamembrane domain of receptor tyrosine kinase FLT3 occur frequently in patients with acute myeloid leukemia (AML). Constitutive active FLT3-ITD mutations induce aberrant signaling and promote leukemic cell transformation. Inactivation of the attenuating receptor protein tyrosine phosphatase CD45 (PTPRC) in FLT3-ITD mice resulted in the development of a severe hematopoietic phenotype with characteristics of AML. In addition, abnormal bone structures and ectopic bone formation were observed in these mice, suggesting a previously unknown role of FLT3 to control bone development and remodeling. While Ptprc knockout and Flt3-ITD mutant mice showed a largely normal bone microarchitecture, micro-CT analysis of femurs from Flt3-ITD Ptprc knockout mice revealed trabecularization of the cortical bone. This resulted in increased trabecular bone volume at the metaphysis, while the cortical bone at the diaphysis was thinner and less dense. In the metaphysis, severely reduced osteoclast and osteoblast numbers were observed. Reduced capacity of ex vivo differentiation of CD11b-positive bone marrow stem cells to mature osteoclast was accompanied by their abnormal morphology and reduced size. Transcriptome analysis revealed reduced expression of osteoclastogenic genes. Unexpectedly, cumulative resorption activity of osteoclasts was increased. Size and structure of resorption pits of differentiated osteoclasts remained similar to those observed in osteoclast cultures derived from control animals. Enhanced proliferation of cells in osteoclast cultures derived from FLT3-ITD-expressing mice was mediated by increased expression of STAT5 target genes. Transcriptome analysis of differentiated osteoclasts showed dysregulated signaling pathways influencing their differentiation as well as the coupling of bone resorption and formation. Taken together, inactivation of attenuating CD45 in mice expressing oncogenic FLT3-ITD resulted in marked abnormalities of the osteo-hematopoietic niche, which can be explained by aberrant STAT5 activation.

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