Significant Inverse Correlation of Serum Levels of Osteoprotegerin (OPG) and Transferrin Saturation in Thalassemia Dependent Transfusion (TDT) Patients.

BACKGROUND: Osteoporosis is a major problem in transfusion-dependent thalassemia patients (TDT) patients. Osteoprotegerin (OPG) is one of several bone markers that are closely associated with osteoporosis in TDT patients. OPG is a glycoprotein that functions as a feedback receptor for the Receptor Activator of Nuclear Factor kappa B Ligand (RANKL), which is an alpha tumor necrosis factor receptor. One of the causes of decreased bone mass density is iron toxicity, which can be identified by showing elevated transferrin saturation. Bone mass dual X-ray absorptiometry (DEXA) is a gold standard for the diagnosis of osteoporosis, these procedures are not commonly available in Indonesia. This study was conducted to analyze the correlation between serum levels of OPG and transferrin saturation in TDT patients. METHODS: A correlational study with a cross-sectional approach analyzed data from TDT patients at Hemato-Oncology Medic Outpatient Clinic, Hasan Sadikin General Hospital, Bandung, Indonesia. Primary data were obtained through blood sampling and anthropometry measurement while secondary data were obtained from the patient's medical records. OPG and transferrin saturation levels were assessed using the ELISA method. Research data were analyzed using the rank Spearman correlation test. RESULTS: Data were collected from 51 research subjects (30 women dan 21 men). The median OPG level was 380 (170-1230) pg/mL and the median transferrin saturation level was 89.4 (66.7 - 96.2)%. Analysis of correlation showed a significant correlation between and transferrin saturation level with a coefficient value of r -0.539 and p-value <0.001. CONCLUSION: There was a significant inverse correlation between OPG with transferrin saturation in TDT patients.

The Relationship Among Probable SARCopenia, Osteoporosis and SuprasPinatus Tendon Tears in Postmenopausal Women: The SARCOSP Study.

We aimed to investigate the relationship among probable sarcopenia, osteoporosis (OP) and supraspinatus tendon (SSP) tears in postmenopausal women. Postmenopausal women screened/followed for OP were recruited. Demographic data, comorbidities, exercise/smoking status, and handgrip strength values were recorded. Probable sarcopenia was diagnosed as handgrip strength values < 20 kg. Achilles and SSP thicknesses were measured using ultrasound. Among 1443 postmenopausal women, 268 (18.6%) subjects had SSP tears. Unilateral tears were on the dominant side in 146 (10.1%) and on the non-dominant side in 55 women (3.8%). In contrast to those without, women with SSP tears had older age, lower level of education, thinner SSP and lower grip strength (all p < 0.05). In addition, they had higher frequencies of hypertension, hyperlipidemia, DM, OP and probable sarcopenia, but lower exercise frequency (all p < 0.05). Binary logistic regression modeling revealed that age [odds ratio (OR): 1.046 (1.024-1.067 95% CI)], hypertension [OR: 1.560 (1.145-2.124 95% CI)], OP [OR: 1.371 (1.022-1.839 95% CI)] and probable sarcopenia [OR: 1.386 (1.031-1.861 95% CI)] were significant predictors for SSP tears (all p < 0.05). This study showed that age, presence of hypertension, probable sarcopenia and OP were related with SSP tears in postmenopausal women. To this end, although OP appeared to be related to SSP tears, SSP tear/thickness evaluation can be recommended for OP patients, especially those who have other risk factors such as older age, higher BMI, hypertension, and probable sarcopenia.

Cichoric acid targets RANKL to inhibit osteoclastogenesis and prevent ovariectomy-induced bone loss.

BACKGROUND AND AIM: Osteoporosis, a systemic metabolic bone disease, is characterized by the decline of bone mass and quality due to excessive osteoclast activity. Currently, drug-targeting osteoclasts show promising therapy for osteoporosis. In this study, we investigated the effect of cichoric acid (CA) on receptor activator of nuclear kappa-B ligand (RANKL)-induced osteoclastogenesis and the bone loss induced by ovariectomy in mice. EXPERIMENTAL PROCEDURE: Molecular docking technologies were employed to examine the interaction between CA and RANKL. CCK8 assay was used to evaluate the cell viability under CA treatment. TRAcP staining, podosome belt staining, and bone resorption assays were used to test the effect of CA on osteoclastogenesis and osteoclast function. Further, an OVX-induced osteoporosis mice model was employed to identify the effect of CA on bone loss using micro-CT scanning and histological examination. To investigate underlying mechanisms, network pharmacology was applied to predict the downstream signaling pathways, which were verified by Western blot and immunofluorescence staining. KEY RESULTS: The molecular docking analysis revealed that CA exhibited a specific binding affinity to RANKL, engaging multiple binding sites. CA inhibited RANKL-induced osteoclastogenesis and bone resorption without cytotoxic effects. Mechanistically, CA suppressed RANKL-induced intracellular reactive oxygen species, nuclear factor-kappa B, and mitogen-activated protein kinase pathways, followed by abrogated nuclear factor activated T-cells 1 activity. Consistent with this finding, CA attenuated post-ovariectomy-induced osteoporosis by ameliorating osteoclastogenesis. CONCLUSIONS AND IMPLICATIONS: CA inhibited osteoclast activity and bone loss by targeting RANKL. CA might represent a promising candidate for treating osteoclast-related diseases, such as osteoporosis.

Mitochondrial dysfunction and therapeutic perspectives in osteoporosis.

Osteoporosis (OP) is a systemic skeletal disorder characterized by reduced bone mass and structural deterioration of bone tissue, resulting in heightened vulnerability to fractures due to increased bone fragility. This condition primarily arises from an imbalance between the processes of bone resorption and formation. Mitochondrial dysfunction has been reported to potentially constitute one of the most crucial mechanisms influencing the pathogenesis of osteoporosis. In essence, mitochondria play a crucial role in maintaining the delicate equilibrium between bone formation and resorption, thereby ensuring optimal skeletal health. Nevertheless, disruption of this delicate balance can arise as a consequence of mitochondrial dysfunction. In dysfunctional mitochondria, the mitochondrial electron transport chain (ETC) becomes uncoupled, resulting in reduced ATP synthesis and increased generation of reactive oxygen species (ROS). Reinforcement of mitochondrial dysfunction is further exacerbated by the accumulation of aberrant mitochondria. In this review, we investigated and analyzed the correlation between mitochondrial dysfunction, encompassing mitochondrial DNA (mtDNA) alterations, oxidative phosphorylation (OXPHOS) impairment, mitophagy dysregulation, defects in mitochondrial biogenesis and dynamics, as well as excessive ROS accumulation, with regards to OP (Figure 1). Furthermore, we explore prospective strategies currently available for modulating mitochondria to ameliorate osteoporosis. Undoubtedly, certain therapeutic strategies still require further investigation to ensure their safety and efficacy as clinical treatments. However, from a mitochondrial perspective, the potential for establishing effective and safe therapeutic approaches for osteoporosis appears promising.

Demonstration of magnetic resonance Z-spectral imaging for fatty acid characterization of bone marrow at 3 T.

Magnetic resonance Z-spectral imaging (ZSI) has emerged as a new approach to measure fat fraction (FF). However, its feasibility for fat spectral imaging remains to be elucidated. In this study, a single-slice ZSI sequence dedicated to fat spectral imaging was designed, and its capability for fatty acid characterization was investigated on peanut oil samples, a multiple-vial fat-water phantom with varied oil volumes, and vertebral body marrow in healthy volunteers and osteoporosis patients at 3 T. The peanut oil spectrum was also recorded with a 400-MHz NMR spectrometer. A Gaussian-Lorentzian sum model was used to resolve water and six fat signals of the pure oil sample or four fat signals of the fat-water phantom or vertebral bone marrow from Z spectra. Fat peak amplitudes were normalized to the total peak amplitude of water and all fat signals. Normalized fat peak amplitudes and FF were quantified and compared among vials of the fat-water phantom or between healthy volunteers and osteoporosis patients. An unpaired student's t-test and Pearson's correlation were conducted, with p less than 0.05 considered statistically significant. The results showed that the peanut oil spectra measured with the ZSI technique were in line with respective NMR spectra, with amplitudes of the six fat signal peaks significantly correlated between the two methods (y = x + 0.001, r = 0.996, p < 0.001 under a repetition time of 1.6 s; and y = 1.026x - 0.003, r = 0.996, p < 0.001 under a repetition time of 3.1 s). Moreover, ZSI-measured FF exhibited a significant correlation with prepared oil volumes (y = 0.876x + 1.290, r = 0.996, p < 0.001). The osteoporosis patients showed significantly higher normalized fat peak amplitudes and FF in the L4 vertebral body marrow than the healthy volunteers (all p < 0.01). In summary, the designed ZSI sequence is feasible for fatty acid characterization, and has the potential to facilitate the diagnosis and evaluation of diseases associated with fat alterations at 3 T.

Restoring implant fixation strength in osteoporotic bone with a hydrogel locally delivering zoledronic acid and bone morphogenetic protein 2. A longitudinal in vivo microCT study in rats.

Osteoporosis poses a major public health challenge, and it is characterized by low bone mass, deterioration of the microarchitecture of bone tissue, causing a consequent increase in bone fragility and susceptibility to fractures and complicating bone fixation, particularly screw implantation. In the present study, our aim was to improve implant stability in osteoporotic bone using a thermoresponsive hyaluronan hydrogel (HA-pNIPAM) to locally deliver the bisphosphonate zoledronic acid (ZOL) to prevent bone resorption and bone morphogenetic protein 2 (BMP2) to induce bone formation. Adult female Wistar rats (n = 36) were divided into 2 treatment groups: one group of SHAM-operated animals and another group that received an ovariectomy (OVX) to induce an osteoporotic state. All animals received a polyetheretherketone (PEEK) screw in the proximal tibia. In addition, subgroups of SHAM or OVX animals received either the HA-pNIPAM hydrogel without or with ZOL/BMP2, placed into the defect site prior to screw implantation. Periprosthetic bone and implant fixation were monitored using longitudinal in vivo microCT scanning post-operatively and at 3, 6, 9, 14, 20 and 28 days. Histological assessment was performed post-mortem. Our data showed that pure hydrogel has no impact of implant fixation The ZOL/BMP2-hydrogel significantly increased bone-implant contact and peri-implant bone fraction, primarily through reduced resorption. STATEMENT OF CLINICAL SIGNIFICANCE: Local delivery of ZOL and BMP2 using a biocompatible hydrogel improved implant stability in osteoporotic bone. This approach could constitute a potent alternative to systemic drug administration and may be useful in avoiding implant loosening in clinical settings.

Clinical Use of Trabecular Bone Score: The 2023 ISCD Official Positions.

Osteoporosis can currently be diagnosed by applying the WHO classification to bone mineral density (BMD) assessed by dual-energy x-ray absorptiometry (DXA). However, skeletal factors other than BMD contribute to bone strength and fracture risk. Lumbar spine TBS, a grey-level texture measure which is derived from DXA images has been extensively studied, enhances fracture prediction independent of BMD and can be used to adjust fracture probability from FRAX® to improve risk stratification. The purpose of this International Society for Clinical Densitometry task force was to review the existing evidence and develop recommendations to assist clinicians regarding when and how to perform, report and utilize TBS. Our review concluded that TBS is most likely to alter clinical management in patients aged ≥ 40 years who are close to the pharmacologic intervention threshold by FRAX. The TBS value from L1-L4 vertebral levels, without vertebral exclusions, should be used to calculate adjusted FRAX probabilities. L1-L4 vertebral levels can be used in the presence of degenerative changes and lumbar compression fractures. It is recommended not to report TBS if extreme structural or pathological artifacts are present. Monitoring and reporting TBS change is unlikely to be helpful with the current version of the TBS algorithm. The next version of TBS software will include an adjustment based upon directly measured tissue thickness. This is expected to improve performance and address some of the technical factors that affect the current algorithm which may require modifications to these Official Positions as experience is acquired with this new algorithm.

Effects of emulsified and non-emulsified palm tocotrienol on bone and joint health in ovariectomised rats with monosodium iodoacetate-induced osteoarthritis.

Postmenopausal women are susceptible to osteoporosis and osteoarthritis. Tocotrienol, a bone-protective nutraceutical, is reported to prevent osteoarthritis in male rats. However, its efficacy on joint health in oestrogen deficiency has not been validated. Besides, data on the use of emulsification systems in enhancing bioavailability and protective effects of tocotrienol are limited. Ovariectomised adult female Sprague-Dawley rats (3 months old) were treated with refined olive oil, emulsified (EPT, 100 mg/kg/day with 25% vitamin E content), non-emulsified palm tocotrienol (NEPT, 100 mg/kg/day with 50% vitamin E content) and calcium carbonate (1% w/v in drinking water) plus glucosamine sulphate (250 mg/kg/day) for 10 weeks. Osteoarthritis was induced with monosodium iodoacetate four weeks after ovariectomy. Baseline control was sacrificed upon receipt, while the sham group was not ovariectomised and treated with refined olive oil. EPT and NEPT prevented femoral metaphyseal and subchondral bone volume decline caused by ovariectomy. EPT decreased subchondral trabecular separation compared to the negative control. EPT preserved stiffness and Young's Modulus at the femoral mid-shaft of the rats. Circulating RANKL was reduced post-treatment in the EPT group. Joint width was reduced in all the treatment groups vs the negative control. The EPT group's grip strength was significantly improved over the negative control and NEPT group. EPT also preserved cartilage histology based on several Mankin's subscores. EPT performed as effectively as NEPT in preventing osteoporosis and osteoarthritis in ovariectomised rats despite containing less vitamin E content. This study justifies clinical trials for the use of EPT in postmenopausal women with both conditions.

Eldecalcitol prevents muscle loss and osteoporosis in disuse muscle atrophy via NF-κB signaling in mice.

We investigated the effect of eldecalcitol on disuse muscle atrophy. C57BL/6J male mice aged 6 weeks were randomly assigned to control, tail suspension (TS), and TS-eldecalcitol-treated groups and were injected intraperitoneally twice a week with either vehicle (control and TS) or eldecalcitol at 3.5 or 5 ng for 3 weeks. Grip strength and muscle weights of the gastrocnemius (GAS), tibialis anterior (TA), and soleus (SOL) were determined. Oxidative stress was evaluated by malondialdehyde, superoxide dismutase, glutathione peroxidase, and catalase. Bone microarchitecture was analyzed using microcomputed tomography. The effect of eldecalcitol on C2C12 myoblasts was analyzed by measuring myofibrillar protein MHC and the atrophy markers Atrogin-1 and MuRF-1 using immunofluorescence. The influence of eldecalcitol on NF-κB signaling pathway and vitamin D receptor (VDR) was assessed through immunofluorescence, (co)-immunoprecipitation, and VDR knockdown studies. Eldecalcitol increased grip strength (P < 0.01) and restored muscle loss in GAS, TA, and SOL (P < 0.05 to P < 0.001) induced by TS. An improvement was noted in bone mineral density and bone architecture in the eldecalcitol group. The impaired oxidative defense system was restored by eldecalcitol (P < 0.05 to P < 0.01 vs. TS). Eldecalcitol (10 nM) significantly inhibited the expression of MuRF-1 (P < 0.001) and Atrogin-1 (P < 0.01), increased the diameter of myotubes (P < 0.05), inhibited the expression of P65 and P52 components of NF-κB and P65 nuclear location, thereby inhibiting NF-κB signaling. Eldecalcitol promoted VDR binding to P65 and P52. VDR signaling is required for eldecalcitol-mediated anti-atrophy effects. In conclusion, eldecalcitol exerted its beneficial effects on disuse-induced muscle atrophy via NF-κB inhibition.

Micropetrosis: Osteocyte Lacunar Mineralization in Aging and Disease.

PURPOSE OF REVIEW: As the importance of osteocytes for bone mineral homeostasis is increasingly recognized, there is growing interest in osteocyte cell death as a relevant indicator in various physiological and pathological conditions. Micropetrosis is an established term used to describe osteocyte lacunae that are filled with minerals following osteocyte death. While the early reports of micropetrosis were purely descriptive, there is now an increasing body of literature showing quantitative data on micropetrosis in various conditions such as aging, osteoporosis, immobilization, and diabetes, and in osteoporosis treatment (denosumab and bisphosphonates). This review summarizes quantitative findings on micropetrosis, with a particular emphasis on the recent advances in the field. RECENT FINDINGS: There is growing evidence that micropetrosis is more common in older, osteoporotic, and immobilized individuals, as well as in individuals with type 1 or type 2 diabetes. Denosumab and bisphosphonates seem to affect lacunar mineralization differently, where specifically bisphosphonates have been shown to prolong osteocyte viability and reduce micropetrosis. Despite continuous proceedings in the field of osteocyte-lacunar-network characteristics, more studies are necessary to further clarify the mechanisms of lacunar mineralization, the inter-site variability of micropetrosis accumulation, the relevance of micropetrosis in various diseases and conditions, and whether micropetrosis could be an indicator of bone fragility or a target for treatment.

SGMS2 in primary osteoporosis with facial nerve palsy.

Pathogenic heterozygous variants in SGMS2 cause a rare monogenic form of osteoporosis known as calvarial doughnut lesions with bone fragility (CDL). The clinical presentations of SGMS2-related bone pathology range from childhood-onset osteoporosis with low bone mineral density and sclerotic doughnut-shaped lesions in the skull to a severe spondylometaphyseal dysplasia with neonatal fractures, long-bone deformities, and short stature. In addition, neurological manifestations occur in some patients. SGMS2 encodes sphingomyelin synthase 2 (SMS2), an enzyme involved in the production of sphingomyelin (SM). This review describes the biochemical structure of SM, SM metabolism, and their molecular actions in skeletal and neural tissue. We postulate how disrupted SM gradient can influence bone formation and how animal models may facilitate a better understanding of SGMS2-related osteoporosis.

Disturbed bone marrow adiposity in patients with Cushing's syndrome and glucocorticoid- and postmenopausal- induced osteoporosis.

Background: Skeletal stem/progenitor cells (SSPCs) in the bone marrow can differentiate into osteoblasts or adipocytes in response to microenvironmental signalling input, including hormonal signalling. Glucocorticoids (GC) are corticosteroid hormones that promote adipogenic differentiation and are endogenously increased in patients with Cushing´s syndrome (CS). Here, we investigate bone marrow adiposity changes in response to endogenous or exogenous GC increases. For that, we characterize bone biopsies from patients with CS and post-menopausal women with glucocorticoid-induced osteoporosis (GC-O), compared to age-matched controls, including postmenopausal osteoporotic patients (PM-O). Methods: Transiliac crest bone biopsies from CS patients and healthy controls, and from postmenopausal women with GC-O and matched controls were analysed; an additional cohort included biopsies from women with PM-O. Plastic-embedded biopsies were sectioned for histomorphometric characterization and quantification of adipocytes. The fraction of adipocyte area per tissue (Ad.Ar/T.Ar) and marrow area (Ad.Ar/Ma.Ar), mean adipocyte profile area (Ad.Pf.Ar) and adipocyte profile density (N.Ad.Pf/Ma.Ar) were determined and correlated to steroid levels. Furthermore, the spatial distribution of adipocytes in relation to trabecular bone was characterized and correlations between bone marrow adiposity and bone remodeling parameters investigated. Results: Biopsies from patients with CS and GC-O presented increased Ad.Ar/Ma.Ar, along with adipocyte hypertrophy and hyperplasia. In patients with CS, both Ad.Ar/Ma.Ar and Ad.Pf.Ar significantly correlated with serum cortisol levels. Spatial distribution analyses revealed that, in CS, the increase in Ad.Ar/Ma.Ar near to trabecular bone (<100 µm) was mediated by both adipocyte hypertrophy and hyperplasia, while N.Ad.Pf/Ma.Ar further into the marrow (>100 µm) remained unchanged. In contrast, patients with GC-O only presented increased Ad.Ar/Ma.Ar and mean Ad.Pf.Ar>100 µm from trabecular bone surface, highlighting the differential effect of increased endogenous steroid accumulation. Finally, the Ad.Ar/Ma.Ar and Ad.Ar/T.Ar correlated with the canopy coverage above remodeling events. Conclusion: Increased cortisol production in patients with CS induces increased bone marrow adiposity, primarily mediated by adipocyte hypertrophy. This adiposity is particularly evident near trabecular bone surfaces, where hyperplasia also occurs. The differential pattern of adiposity in patients with CS and GC-O highlights that bone marrow adipocytes and their progenitors may respond differently in these two GC-mediated bone diseases.

Fracture healing in a mouse model of Hajdu-Cheney-Syndrome with high turnover osteopenia results in decreased biomechanical stability.

Notch signaling regulates cell fate in multiple tissues including the skeleton. Hajdu-Cheney-Syndrome (HCS), caused by gain-of-function mutations in the Notch2 gene, is a rare inherited disease featuring early-onset osteoporosis and increased risk for fractures and non-union. As the impact of Notch2 overactivation on fracture healing is unknown, we studied bone regeneration in mice harboring a human HCS mutation. HCS mice, displaying high turnover osteopenia in the non-fractured skeleton, exhibited only minor morphologic alterations in the progression of bone regeneration, evidenced by static radiological and histological outcome measurements. Histomorphometry showed increased osteoclast parameters in the callus of HCS mice, which was accompanied by an increased expression of osteoclast and osteoblast markers. These observations were accompanied by inferior biomechanical stability of healed femora in HCS mice. Together, our data demonstrate that structural indices of bone regeneration are normal in HCS mice, which, however, exhibit signs of increased callus turnover and display impaired biomechanical stability of healed fractures.

Leptin and melatonin's effects on OVX rodents' bone metabolism.

Purpose: This study aims to examine the effects of leptin and melatonin intervention on bone metabolism in ovariectomize (OVX) rodents, as well as their potential mechanisms of action. Methods: Prepare an OVX model of osteoporosis in rodents and validate the model by collecting bilateral tibia samples for Micro-CT scanning and histological analysis. A control group of normal size, the OVX group, the OVX+Sema4D (Semaphorin 4D) group, the OVX+Sema4D+Leptin group, the OVX+Sema4D+ Melatonin(MT) group and the OVX+Sema4D+Leptin+ MT group were the experimental groups. Adenovirus vector construction and tibial medullary injection validation were conducted in accordance with the aforementioned experimental groups. Four groups of rats were injected with the Sema4D overexpression adenovirus vector into the tibial medullary cavity, and two groups were injected with the Leptin overexpression adenovirus vector. The repair of osteoporosis was observed using micro-CT and histological analysis. Immunohistochemical detection of bone morphogenetic protein-2 (BMP-2) expression in bone tissue was employed to ascertain the amount of osteoclasts in the upper tibial metaphysis, utilizing TRAP(tartrate-resistant acid phosphatase) staining. Results: Increased levels of BV/TV, Tb.N, BMD, and BMC were seen in the OVX+ Sema4D+Leptin, OVX+ Sema4D+MT, and OVX+ Sema4D+Leptin+ MT groups compared to the OVX group, whereas Tb. Sp levels were lowered. When compared to the Sema4D overexpression group, the trabecular bone structure of the OVX + Sema4D + Leptin, OVX + Sema4D + MT, and OVX + Sema4D + Leptin + MT groups is largely intact, tends to be closer, and the amount of trabecular bone increases. The OVX + Sema4D + Leptin + MT group in particular.The expression of BMP-2 was dramatically upregulated (p<0.05), the number of TRAP-stained osteoclasts was significantly reduced (p<0.05), and BALP(bone-derived alkaline phosphatase) and TRAP-5b(tartrate-resistant acid phosphatase-5b) activities were significantly downregulated (p<0.05). Conclusion: In rats with osteoporosis, leptin and melatonin can be seen to augment the trabecular microstructure of the bone, augment bone growth, diminish trabecular harm, and mend the bone. The combined effect is more powerful.

The intricate mechanism of PLS3 in bone homeostasis and disease.

Since our discovery in 2013 that genetic defects in PLS3 lead to bone fragility, the mechanistic details of this process have remained obscure. It has been established that PLS3 variants cause syndromic and nonsyndromic osteoporosis as well as osteoarthritis. PLS3 codes for an actin-bundling protein with a broad pattern of expression. As such, it is puzzling how PLS3 specifically leads to bone-related disease presentation. Our review aims to summarize the current state of knowledge regarding the function of PLS3 in the predominant cell types in the bone tissue, the osteocytes, osteoblasts and osteoclasts. This is related to the role of PLS3 in regulating mechanotransduction, calcium regulation, vesicle trafficking, cell differentiation and mineralization as part of the complex bone pathology presented by PLS3 defects. Considering the consequences of PLS3 defects on multiple aspects of bone tissue metabolism, our review motivates the study of its mechanism in bone diseases which can potentially help in the design of suitable therapy.

Strontium-driven physiological to pathological transition of bone-like architecture: A dose-dependent investigation.

Whilst strontium (Sr2+) is widely investigated for treating osteoporosis, it is also related to mineralization disorders such as rickets and osteomalacia. In order to clarify the physiological and pathological effects of Sr2+ on bone biomineralization , we performed a dose-dependent investigation in bone components using a 3D scaffold that displays the hallmark features of bone tissue in terms of composition (osteoblast, collagen, carbonated apatite) and architecture (mineralized collagen fibrils hierarchically assembled into a twisted plywood geometry). As the level of Sr2+ is increased from physiological-like to excess, both the mineral and the collagen fibrils assembly are destabilized, leading to a drop in the Young modulus, with strong implications on pre-osteoblastic cell proliferation. Furthermore, the microstructural and mechanical changes reported here correlate with that observed in bone-weakening disorders induced by Sr2+ accumulation, which may clarify the paradoxical effects of Sr2+ in bone mineralization. More generally, our results provide physicochemical insights into the possible effects of inorganic ions on the assembly of bone extracellular matrix and may contribute to the design of safer therapies for treating osteoporosis. STATEMENT OF SIGNIFICANCE: Physiological-like (10% Sr2+) and excess accumulation-like (50% Sr2+) doses of Sr2+ are investigated in 3D biomimetic assemblies possessing the high degree of organization found in the extracellular of bone. Above the physiological dose, the organic and inorganic components of the bone-like scaffold are destabilized, resulting in impaired cellular activity, which correlates with bone-weakening disorders induced by Sr2+.

Fgfr1 deficiency in osteocytes leads to increased bone mass by enhancing Wnt/ß-catenin signaling.

Osteoporosis (OP) is the most common skeletal disease in middle-aged and elderly people. A comprehensive understanding of the pathogenesis of osteoporosis is important. Fibroblast growth factor receptor 1 (FGFR1) is an important molecule for skeletal development and bone remodeling. Osteocytes are the most numerous cells in bone and play critical roles in bone homeostasis, however the effect of FGFR1 on osteocytes is still unclear. To clarify the direct effects of FGFR1 on osteocytes, we conditionally deleted Fgfr1 in osteocytes with Dentin matrix protein 1 (Dmp1)-Cre. We found that mice lacking Fgfr1 in osteocytes (Fgfr1f/f;Dmp-cre, MUT) showed increased trabecular bone mass at 2 and 6 months of age, which resulted from enhanced bone formation and decreased bone resorption. Furthermore, the cortical bone was thicker in WT mice than that in MUT mice at 2 and 6 months of age. Histological analysis showed that MUT mice had a decreased number of osteocytes but an increased number of osteocyte dendrites. We further found that mice lacking Fgfr1 in osteocytes showed enhanced activation of ß-catenin signaling. The expression of sclerostin, an inhibitor of Wnt/ß-catenin signaling, was obviously decreased in MUT mice. Furthermore, we found that FGFR1 can inhibit the expression of ß-catenin and decrease the activity of ß-catenin signaling. In brief, our study showed that FGFR1 in osteocytes can regulate bone mass by regulating Wnt/ß-catenin signaling, providing genetic evidence that FGFR1 plays essential roles in osteocytes during bone remodeling and suggesting that FGFR1 is a potential therapeutic target for the prevention of bone loss.

Fracture risks and their mechanisms in atopic dermatitis, focusing on receptor activator of nuclear factor kappa-B ligand.

Recent multiple studies have shown that the long-term consequences of atopic dermatitis (AD) include an increased risk of osteoporosis and fracture, especially an increase in hip, pelvic, spinal and wrist fractures. AD is very common worldwide, and some kinds of fractures, such as hip fractures, are associated with increased mortality, which has a substantial socioeconomic impact; however, the precise mechanisms for this remain unclear. Receptor activator of nuclear factor kappa-Β (RANK) ligand (RANKL) and osteoprotegerin (OPG) are members of the tumour necrosis factor ligand and receptor family, members of which also are known as bone biomarkers. Alterations in the RANKL/RANK/OPG system and the balance among these factors (represented by the RANKL/OPG ratio) are central to the pathogenesis of bone loss from osteoporosis, and it is postulated that there is a potential association between the serum levels of RANKL and OPG, and bone density or fracture. Recently, our research group demonstrated that the serum RANKL/OPG ratio positively correlated with AD severity and suggests fracture risk in older women with AD. This review summarizes and discusses the risk and mechanisms of osteoporotic fracture in AD. RANKL may be involved in the pathogenesis of AD, regarding not only bone abnormality but also inflammation. Although further investigation will be needed to verify the hypotheses, recent findings may provide new insights into the pathogenesis of AD and therapeutic targets.

Comparisons of gene expression between peripheral blood mononuclear cells and bone tissue in osteoporosis.

Osteoporosis (OP) is one of the major public health problems in the world. However, the biomarkers between the peripheral blood mononuclear cells (PBMs) and bone tissue for prognosis of OP have not been well characterized. This study aimed to explore the similarities and differences of the gene expression profiles between the PBMs and bone tissue and identify potential genes, transcription factors (TFs) and hub proteins involved in OP. The patients were enrolled as an experimental group, and healthy subjects served as normal controls. Human whole-genome expression chips were used to analyze gene expression profiles from PBMs and bone tissue. And the differentially expressed genes (DEGs) were subsequently studied using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. The above DEGs were constructed into protein-protein interaction network. Finally, TF-DEGs regulation networks were constructed. Microarray analysis revealed that 226 DEGs were identified between OP and normal controls in the PBMs, while 2295 DEGs were identified in the bone tissue. And 13 common DEGs were obtained by comparing the 2 tissues. The Gene Ontology analysis indicated that DEGs in the PBMs were more involved in immune response, while DEGs in bone were more involved in renal response and urea transmembrane transport. And the Kyoto Encyclopedia of Genes and Genomes analysis indicated almost all of the pathways in the PBMs were overlapped with those in the bone tissue. Furthermore, protein-protein interaction network presented 6 hub proteins: PI3K1, APP, GNB5, FPR2, GNG13, and PLCG1. APP has been found to be associated with OP. Finally, 5 key TFs were identified by TF-DEGs regulation networks analysis (CREB1, RUNX1, STAT3, CREBBP, and GLI1) and were supposed to be associated with OP. This study enhanced our understanding of the pathogenesis of OP. PI3K1, GNB5, FPR2, GNG13, and PLCG1 might be the potential targets of OP.

Irisin Protects against Loss of Trabecular Bone Mass and Strength in Adult Ovariectomized Mice by Stimulating Osteoblast Activity.

Irisin is a peptide secreted by skeletal muscle that plays a major role in bone metabolism. Experiments in mouse models have shown that administration of recombinant irisin prevents disuse-induced bone loss. In this study, we aimed to evaluate the effects of irisin treatment for the prevention of bone loss in the ovariectomized (Ovx) mouse, the animal model commonly used to investigate osteoporosis caused by estrogen deficiency. Micro-Ct analysis conducted on Sham mice (Sham-veh) and Ovx mice treated with vehicle (Ovx-veh) or recombinant irisin (Ovx-irisn) showed bone volume fraction (BV/TV) decreases in femurs (Ovx-veh 1.39± 0.71 vs. Sham-veh 2.84 ± 1.23; p = 0.02) and tibia at both proximal condyles (Ovx-veh 1.97 ± 0.68 vs. Sham-veh 3.48 ± 1.26; p = 0.03) and the subchondral plate (Ovx-veh 6.33 ± 0.36 vs. Sham-veh 8.18 ± 0.41; p = 0.01), which were prevented by treatment with a weekly dose of irisin for 4 weeks. Moreover, histological analysis of trabecular bone showed that irisin increased the number of active osteoblasts per bone perimeter (Ovx-irisin 32.3 ± 3.9 vs. Ovx-veh 23.5 ± 3.6; p = 0.01), while decreasing osteoclasts (Ovx-irisin 7.6 ± 2.4 vs. Ovx-veh 12.9 ± 3.04; p = 0.05). The possible mechanism by which irisin enhances osteoblast activity in Ovx mice is upregulation of the transcription factor Atf4, one of the key markers of osteoblast differentiation, and osteoprotegerin, thereby inhibiting osteoclast formation.