Calcified Tissue International最新文献

This study describes the potential of the conditioned medium (CM) from adipose-derived mesenchymal stromal cells (ASCs) to affect the response of bone cells and support bone remodeling. This was in particular assessed by an in vitro model represented by a 3D human osteoblast-osteoclast co-culture. It has been reported that the effects of ASCs are predominantly attributable to the paracrine effects of their secreted factors, that are present as soluble factors or loaded into extracellular vesicles. They may affect various biological processes, including bone turnover. Our interest was to provide further evidence to support ASC-CM as a promising cell-free therapeutic agent for the treatment of bone loss. ASC-CM was characterized using nanoparticle tracking analysis (NTA), cytofluorimetry, and proteomic analysis. Human osteoblasts (hOBs) from vertebral lamina were cultured with monocytes, as osteoclasts (hOCs) precursors, in a Rotary cell culture system for 14 days. Histochemical analysis was performed to evaluate the effect of ASC-CM on bone-specific markers such as tartrate-resistant acid phosphatase (TRAP), osteopontin (OPN), RUNX2, Collagen 1 (COL1), and mineral matrix. ASC-CM characterization confirmed the content of CD63/CD81/CD9 positive extracellular vesicles. Proteomic dataset considering bone-remodeling-related keywords identified 16 processes significantly enriched. The exposure of hOBs/hOCs aggregates to ASC-CM induced increase of OPN, COL I, and RUNX2, and significantly induced mineral matrix deposition, while significantly reducing TRAP expression. These data demonstrated that CM from ASCs contains a complex of secreted factors able to control either bone resorption or bone formation and requires further investigations to deeply analyze their potential therapeutic effects.

Pentosidine (PEN), a surrogate marker of advanced glycation end-product formation, reflects increased non-enzymatic cross-linking in bone collagen, which is thought to be an important determinant of bone fragility in type 2 diabetes mellitus (T2DM). We aimed to investigate serum concentrations of PEN in patients with T2DM and controls without T2DM and to examine its relationship with bone parameters and metabolic state such as glycaemic control, insulin resistance and body weight. In a cross-sectional study-design, data from postmenopausal women and men with T2DM (n = 110) and controls without T2DM (n = 111) were evaluated. Serum PEN was measured using an ELISA-based assay (CSB-E09415h, Cusabio). In addition, biochemical markers of glucose metabolism and bone turnover markers were measured. Bone mineral density (BMD) was assessed by dual-energy X-ray absorptiometry. After adjustment for age, gender and body mass index (BMI), serum PEN was significantly higher in patients with T2DM compared to controls (p = 0.02) and most prominently in women with T2DM (p = 0.09). We found a strong association of serum PEN concentrations with BMI in the entire study population (R = 0.43, p < 0.001) as well as in patients with T2DM (R = 0.28, p < 0.01). While bone turnover markers were significantly decreased, and BMD increased in patients with T2DM, only weak or no associations were observed between these skeletal surrogate markers and serum PEN. We conclude that serum PEN is strongly associated with BMI with highest levels in obese women with T2DM. Adjustment for patient's weight is needed when evaluating serum PEN levels in patients with T2DM.Clinical Trial Information: NCT02551315.

Obesity is a major public health issue worldwide. Despite various approaches to weight loss, the most effective technique for reducing obesity, as well as diabetes and associated diseases, is bariatric surgery. Increasingly, young women without children are undergoing bariatric surgery, vertical sleeve gastrectomy (VSG) being the most common procedure nowadays. However, despite several reports suggesting bone loss after VSG, little is known about the potential additive effects of gestation and lactation after VSG to bone health. This study investigated the combined effects of pre-gestational VSG and subsequent gestation/lactation on bone metabolism in a rat model fed a high fat high sugar (HFHS) diet, with a focus on bone biomechanics, mass, microarchitecture and material properties. Furthermore, bone mass and remodelling were followed longitudinally by microCT prior to surgery, 4 weeks post-surgery, after weaning and at sacrifice. Significant alterations in bone mass and microarchitecture, characterized by changes in trabecular thickness and number, as well as changes in bone formation and resorption were influenced by both surgery and reproductive demands. Mechanical testing at sacrifice demonstrated compromised long bone fragility, in rat with HFHS regardless of the surgical procedure (Sham or VSG). Furthermore, analysis of bone material properties highlighted potential disruptions in the pattern of bone mineralization in sham and VSG animals fed a HFHS diet. These findings underscore the complex interplay between pre-gestational VSG and subsequent gestation/lactation in modulating bone metabolism in the investigated rat model. The preclinical rat model may help with optimizing surgical strategies and developing targeted interventions to mitigate potential bone-related complications associated with VSG in reproductive-aged individuals.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by hypersecretion of fibroblast growth factor 23 (FGF23) by typically benign phosphaturic mesenchymal tumors (PMTs). FGF23 excess causes chronic hypophosphatemia through renal phosphate losses and decreased production of 1,25-dihydroxy-vitamin-D. TIO presents with symptoms of chronic hypophosphatemia including fatigue, bone pain, weakness, and fractures. Definitive treatment is surgical resection of the PMT with wide margins. Other therapeutic options are necessary when the tumor is unable to be localized, not amenable to complete resection, or when the patient is not a good surgical candidate. Alternative ablative approaches such as radiotherapy, radiofrequency ablation, and cryoablation, have been used with variable success and limited follow up. Medical management is warranted both prior to definitive therapy and in non-operable cases to improve symptoms and allow for bone remineralization. Oral phosphate and calcitriol were the mainstay of medical therapy, however, the development of burosumab, a monoclonal blocking antibody to FGF23, has introduced an approved therapy that improves hypophosphatemia and symptoms in patients with TIO. In select cases, cinacalcet can be an effective adjuvant to phosphate and calcitriol. Continued monitoring for tumor growth is necessary while on medical therapy. Infigratinib, a selective FGFR tyrosine-kinase inhibitor targeting a causative tumoral fusion protein, can reverse the biochemical findings of TIO and possibly reduce tumor mass; however, its use is constrained by serious side effects. Overall, innovations in medical and interventional treatments have broadened therapeutic options for patients with PMTs, particularly in cases where a curative surgical resection is not possible.

This study explores FD/MAS patient's perceptions about their disease and its impact on their quality of life. We have evaluated quality of life (QoL) in French Fibrous Dysplasia/MacCune-Albright Syndrome (FD/MAS) patients using a qualitative approach with focus groups to explore perceptions, symptoms and limitations associated with FD/MAS and a quantitative method with the Short Form-36 (SF36) to quantify QoL. Focus groups revealed the heterogeneity of FD forms and allowed for understanding the reasons of reduced QoL. Patients identified pain as the dominant symptom. The impact on mental health was explained by diagnostic uncertainty, disease chronicity and rarity and the inconsistent effectiveness of therapies. Patients talked about disability but also of coping strategies. They expressed their need for comprehensive and multi-disciplinary care from medical and paramedical professionals familiar with their pathology. The quantitative questionnaire SF36 confirmed reduced QoL in these patients compared with the French general population in all sub-domains: physical function (72.1 versus 84.4, p = 0.0001), physical role (60.5 versus 81.1, p = 0.0004), body pain (58.7 versus 72.4, p = 0.0004), general health (50.08 versus 67.6, p < 0.0001), energy (44.58 versus 57.2, p < 0.0001), social function (61.34 versus 80.5, p < 0.0001), emotional role (57.98 versus 81.3, p = 0.0002) and emotional well-being (57.98 versus 81.3, p = 0.0097). Polyostotic patients had poorer QoL compared with monostotic patients. A better understanding of the disease experience and expectations of FD patients will enable practitioners to provide care better adapted to patients' needs, and pave the way for optimizing DF care.

Previous studies suggest social support is associated with musculoskeletal health in later life. We explored this relationship further in community-dwelling older adults, by considering associations between different aspects of social support and musculoskeletal health in community-dwelling adults. Participants from the Hertfordshire Cohort Study reported level of confiding/emotional, practical, and negative support using the Close Persons Questionnaire. Muscle strength was measured by grip strength dynamometry, and physical capability by timed up-and-go, chair rises, and walking speed tests. Bone mineral density (BMD) was assessed using dual-energy x-ray absorptiometry. Linear regression, adjusted for age, sex, body mass index (BMI), alcohol, smoking, physical activity, social class, and diet, was used for analysis. 1842 men and women (mean age 65.7 years) participated. Low emotional support correlated with weaker grip strength and poorer physical capability tests, although estimates were not robust to adjustment for confounders. Low practical support was linked to shorter timed up-and-go (β - 0.171, 95%CI - 0.319, - 0.024) and walking speed times (β - 0.157, 95%CI - 0.306, - 0.007), following adjustment for confounders. Negative support (i.e. the perceived inadequacy of the support received) was associated with lower grip strength (β - 0.145, 95%CI - 0.223, - 0.067) and slower walking speeds (β 0.159, 95%CI 0.004, 0.314). No social support exposures were associated with BMD. Different types of social support are linked to various measures of musculoskeletal health in older adults. Limited requirement for practical support correlated with better physical capability, while negative support correlated with poorer outcomes. No social support measure was associated with BMD.

Osteogenesis imperfecta (OI) is an inheritable skeletal disorder characterized by bone fragility often caused by pathogenic variants in the COL1A1 gene. Current OI mouse models with a glycine substitution in Col1a1 exhibit excessive severity, thereby limiting long-term pathophysiological analysis and drug effect assessments. To address this limitation, we constructed a novel OI mouse model mimicking a patient with OI type III. This was achieved by introducing a G-to-A transversion at nucleotide position 2428 in the Col1a1 gene via CRISPR-Cas9 technology in C57BL/6 J mice. The resulting heterozygous variant mice (Col1a1^G643S/+) displayed reduced body weight and pronounced skeletal abnormalities. Micro-CT analysis at 12 weeks revealed decreased vertebral bone parameters and altered cortical bone characteristics, indicative of bone fragility. Additionally, the abnormalities of the anisotropy, complexity, connectivity, and structure of trabecular bone were revealed. A three-point bending test confirmed the fragility, with reduced displacement and fracture energy in both sexes. Furthermore, we evaluated the effect of 4-phenylbutyric acid on the bone in Col1a1^G643S/+ mice at 12 weeks, observing no significant effects, likely due to the absence of collagen retention in the ER in this model. Despite being a moderate OI model, Col1a1^G643S/+ mice manifest a distinct and fragile bone phenotype, making them suitable for extended studies. This model offers a valuable platform for investigating long-term pathophysiological aspects of OI and assessing the efficacy of potential therapeutic interventions.

Aromatase deficiency (ORPHA:91; OMIM: 613,546) is a rare, autosomal recessive disorder due to loss of function mutations in the CYP19A1 gene, described in both genders with an estimated incidence below 1/1000000. While in female the clinical manifestations generally occur at birth or in early infancy, and mainly involve sexual characteristics, in men clinical signs of aromatase deficiency mostly occur in puberty and especially in late puberty, so that diagnosis is generally established after the second decade due to tall stature, unfused epiphyses and reduced bone mass. Here we review the available information concerning the skeletal and extraskeletal phenotype and the clinical management of bone health in patients with aromatase CYP19A1 gene mutations.

We evaluated the role of Helicobacter pylori (H. pylori)-related chronic gastritis in the development of osteoporosis in a population-based study. A total of 1690 subjects in the cohort of the Research on Osteoarthritis/ osteoporosis Against Disability (ROAD) were investigated, and the association between gastritis and osteoporosis was evaluated by the presence of serologically assessed H. pylori-related chronic gastritis and its stage, based on H. pylori antibody titer and pepsinogen. The presence of the gastritis was associated with significantly lower bone mineral density (BMD) assessed by dual-energy x-ray absorptiometry and a significant risk of lower BMD was observed in femoral neck (adjusted odds ratio [OR]: 0.78, 95% confidence interval [CI]: 061-0.99). The progression of the gastritis appeared to further increase the risk. In the stage of non-atrophic gastritis, the risk of lower BMD was significantly high, especially in a subgroup with higher gastritis activity in the femoral neck (adjusted OR: 0.61, 95% CI: 0.42-0.89). Meanwhile, in the stage of atrophic gastritis, the highest and significant risk of lower BMD was observed in a subgroup with the most extensive and severe atrophy in femoral neck (adjusted OR: 0.62, 95% CI: 0.42-0.91). These results suggest that H. pylori-related chronic gastritis is involved in the risk of osteoporosis, with higher activity of gastritis and more extensive atrophy leading to further increased risk. The serologically assessed stage of the gastritis could be used to identify a high-risk group for osteoporosis in H. pylori-infected subjects from general population.

There is an increasing demand for a suitable bone substitute to replace current clinical gold standard autografts or allografts. Majority of previous studies have focused on the early effects of substitutes on bone formation, while information on their long-term efficacies remains limited. This study investigated the efficacies of natural hydroxyapatite (nHA) derived from oyster shells and synthetic hydroxyapatite mixed with collagen (COL/HA) or chitosan (CS/HA) on bone regeneration and implant fixation in sheep. Titanium implants were inserted into critical-size defects in distal femur condyles bilaterally, and circumferential gaps around implants were filled with substitute materials or allografts (as control). 14 or 24 weeks post-operatively, the implant-bone blocks were harvested and evaluated using microarchitectural, histomorphometric, and mechanical methods. The nHA and COL/HA groups showed significant bone formation at both 14 and 24 weeks. There was a pronounced increase in bone tissue volume and ingrowth into titanium implant's porous surfaces, significantly enhancing mechanical fixation strength at 24 weeks. CS/HA had a limited ability to induce bone formation and implant fixation. We conclude that nHA and COL/HA revealed long-term effects on enhancing bone formation and implant fixation that were at least as good as allograft after 24 weeks, and both nHA and COL/HA appear to be good alternative materials to bone allograft.