Search

It is important for athlete and public health that we continue to develop our understanding of the effects of exercise and nutrition on bone health. Bone turnover markers (BTMs) offer an opportunity to accelerate the progression of bone research by revealing a bone response to exercise and nutrition stimuli far more rapidly than current bone imaging techniques. However, the association between short-term change in the concentration of BTMs and long-term bone health remains ambiguous. Several other limitations also complicate the translation of acute BTM data to applied practice. Importantly, several incongruencies exist between the effects of exercise and nutrition stimuli on short-term change in BTM concentration compared with long-term bone structural outcomes to similar stimuli. There are many potential explanations for these inconsistencies, including that short-term study designs fail to encompass a full remodeling cycle. The current article presents the opinion that data from relatively acute studies measuring BTMs may not be able to reliably inform applied practice aiming to optimize bone health. There are important factors to consider when interpreting or translating BTM data and these are discussed. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the influence of immediate loading on the osseointegration and bone density of implants placed in a healed alveolar bone crest and supporting single crowns. Materials and Methods: Two solid titanium transmucosal mini-implants were placed in the distal regions of the mandible in 14 patients. One mini-implant was immediately functionally loaded, whereas the other was left unloaded. After 2 months of healing, biopsy samples were retrieved and the levels of new bone, old bone, and total bone (new + old) were assessed. Results: Histologic examination was performed on biopsies from 12 patients (n = 12). The new bone-to-implant contact percentage (BIC%) was 40.3% ± 16.8% and 55.1% ± 19.1% (P = .043) at the unloaded and loaded sites, respectively; in addition, the total BIC% was 44.9% ± 17.0% and 59.5% ± 18.8%, respectively (P = .034). The new bone density was 45.9% ± 11.6% for the unloaded implants and 45.9% ± 16.7% for the loaded implants (P = .622). Conclusions: Immediate loading had a positive effect on bone apposition at the implant surface, but no effect on bone density was observed after 2 months of healing. [ABSTRACT FROM AUTHOR]

Bone graft materials are often used in implant treatment to optimize functional and esthetic outcomes. The requirements for bone grafting materials are the ability to maintain space for bone regeneration to occur and the capability of being resorbed by osteoclasts and replaced with new bone tissue occurring in passive chemolysis and bone remodeling. Carbonate apatite (CO3Ap) granules (Cytrans Granules, GC) are a chemically synthetic bone graft material similar to autogenous bone minerals and more biocompatible than allografts and xenografts. The aim of this report is to evaluate the efficacy of CO3Ap granules in implant treatments when used alone or in combination with autogenous bone. The clinical findings and the radiographic and histologic assessments in three cases of immediate implant placement and lateral and vertical guided bone regeneration are reported. Despite the short-term follow-ups, histologic findings showed that CO3Ap granules were efficiently resorbed and replaced bone in clinical use. Furthermore, the clinical findings showed that CO3Ap granules maintained their morphology around the implant. This limited short-term case report suggests that this bone substitute is effective. However, further clinical studies and long-term reports of this new biomaterial are needed. [ABSTRACT FROM AUTHOR]

In lactating mothers, the high calcium (Ca2+) demand for milk production triggers significant bone loss1. Although oestrogen normally counteracts excessive bone resorption by promoting bone formation, this sex steroid drops precipitously during this postpartum period. Here we report that brain-derived cellular communication network factor 3 (CCN3) secreted from KISS1 neurons of the arcuate nucleus (ARCKISS1) fills this void and functions as a potent osteoanabolic factor to build bone in lactating females. We began by showing that our previously reported female-specific, dense bone phenotype2 originates from a humoral factor that promotes bone mass and acts on skeletal stem cells to increase their frequency and osteochondrogenic potential. This circulatory factor was then identified as CCN3, a brain-derived hormone from ARCKISS1 neurons that is able to stimulate mouse and human skeletal stem cell activity, increase bone remodelling and accelerate fracture repair in young and old mice of both sexes. The role of CCN3 in normal female physiology was revealed after detecting a burst of CCN3 expression in ARCKISS1 neurons coincident with lactation. After reducing CCN3 in ARCKISS1 neurons, lactating mothers lost bone and failed to sustain their progeny when challenged with a low-calcium diet. Our findings establish CCN3 as a potentially new therapeutic osteoanabolic hormone for both sexes and define a new maternal brain hormone for ensuring species survival in mammals.

Assessing bone's response to physical activity interventions is challenging. This randomized controlled trial investigates if changes in bone turnover markers can offer an early evaluation of a physical activity intervention's effectiveness in improving bone mineral density (BMD) in premenopausal women. Participants in the intervention group (n = 27, with 24 completing the trial) were instructed to walk at least 10,000 steps every day on a brisk walk and to execute 60 jumps daily, each surpassing 4g of acceleration, using an accelerometer-based wearable device. Meanwhile, the control group (n = 26, with 18 completing the trial) continued with their usual lifestyle. Bone turnover markers, comprising of C-terminal telopeptide of Type I collagen, procollagen Type 1 N-terminal propeptide, and total osteocalcin (carboxylated and undercarboxylated) were measured at baseline and midway through the intervention (3 months). Dual-energy X-ray absorptiometry scans of the hip and lumbar spine were conducted at baseline and the end of the intervention (6 months) to estimate BMD. Analysis of covariance exhibited significant differences between groups in procollagen Type 1 N-terminal propeptide (−6.74 μg/L, p =.023) and C-terminal telopeptide of Type I collagen (−83 ng/L, p =.043) after 3 months, and in femoral neck BMD (+0.024 g/cm2, p =.016), total hip BMD (+0.036 g/cm2, p =.004), and lumbar spine BMD (+0.026 g/cm2, p =.020) after 6 months. A significant correlation (r = −.73; p <.001) was detected between reductions in C-terminal telopeptide of Type I collagen and increases in femoral neck BMD. In conclusion, this intervention improved BMD in premenopausal women, with bone turnover markers potentially useful for early intervention assessment, though further research is needed. [ABSTRACT FROM AUTHOR]

A retrospective chart review was conducted of CBCT images captured between November 2019 and April 2021 on patients who underwent dental implant placement and had a periodontal charting. The buccal and lingual bone thickness around the implants was measured as an average of three measurements taken from the buccal and lingual aspects of implants. Implants with peri-implantitis were placed in Group 1, and implants with peri-implant mucositis or good peri-implant health were placed in Group 2. Wilcoxon rank sum test was used to compare the differences between the bone thicknesses of the groups. In total, 93 CBCT radiographs were screened, and 15 CBCT images with both an implant and corresponding periodontal charting were analyzed. Of the 15 implants examined, 5 presented with peri-implantitis (33%), 1 with peri-implant mucositis, and 9 with good peri-implant health. Within the limitations of this study, buccal bone thickness averaging ≥ 1.10 mm or midlingual probing depths ≥ 3.4 mm correlates with a more favorable peri-implant response. Larger studies are needed to substantiate these findings. [ABSTRACT FROM AUTHOR]

Purpose: To assess two types of abutment materials routinely used in daily practice--direct polymethyl methacrylate (PMMA) and a zirconia-on--Ti-base abutment--and their effects on peri-implant soft tissues and bone remodeling in a minipig model. Materials and Methods: A total of 40 implants were placed in five minipigs in a single-stage surgery. Four different types of abutment materials (n = 10 per group) were used: (1) titanium (control); (2) zirconia (control); (3) PMMA (test 1); and (4) Ti-base (zirconia bonded to a titanium framework; test 2). After 3 months of healing, the samples were collected and subjected to nondecalcified histology. The soft tissue dimensions (sulcus, junctional epithelium, and connective tissue attachment) were assessed on each abutment mesially and distally, and the distance from the implant margin to the first boneto-implant contact (BIC) was measured. Results: No statistically significant differences were found among the four groups regarding soft tissue dimensions (P = .21), and a long junctional epithelium (mean: 4.1 mm) and a short connective tissue attachment (mean: 0.3 mm) were found in the majority of abutments. In some samples, the junctional epithelium extended all the way to the bone level. The measured peri-implant bone remodeling was similar in all four groups (P = .25). Conclusions: The present findings indicate that both direct PMMA and zirconia-on-Ti-base abutments seem to allow soft tissue integration similar to that of titanium and zirconia abutments. However, clinical studies are warranted to either confirm or refute the observed findings and to further investigate the influence of different materials on mucointegration. [ABSTRACT FROM AUTHOR]

This retrospective study evaluated the survival rate and the clinical outcome of an endosseous implant system, as well as the marginal bone level (MBL) and the impact of the machined collar neck position on crestal bone level changes up to 2 years later. A total of 96 implants were placed in 57 patients and loaded with a final restoration after at least 3 months of healing: 15 implants were immediately placed into fresh extraction sockets, and 81 were placed in healed ridges. Marginal bone loss around implants was determined radiographically at 12 to 24 months postloading. The effects on marginal bone loss of the site (mandible vs maxilla), location (anterior vs posterior), immediate vs delayed implant, smoking habit, sex, implant length and diameter, prosthesis type (screw-retained/cemented), and the machined collar position were evaluated. The implant survival rate was 98.96% at 1 year. The mean MBL decreased significantly (0.238 mm) between baseline and loading (P < .001; post hoc test) and decreased by 0.154 mm between loading and 1 year, but this was not significant (P = .085; post hoc tests). After 2 years, the mean MBL decreased significantly (0.263 mm) between baseline and loading (P < .001) and decreased by 0.111 mm between loading and 1 year and by 0.199 mm between loading and 2 years, but these were not significant (P > .05; post hoc tests). The mean bone loss after 1 and 2 years was not significantly associated with implant type or site, smoking habit, or type of implant surgery (P = .792). However, the mean bone loss was significantly associated with the type of prosthesis and was significantly greater for cemented prostheses compared to screw-retained prostheses. A supracrestal position of the machined collar (tissue level) was associated with no bone loss, while placing the collar below the alveolar crest led to bone loss over 2 years. Of the factors evaluated, marginal bone loss after 1 and 2 years was significantly associated with prosthesis type and the machined collar position. [ABSTRACT FROM AUTHOR]

Purpose: To examine the remodeling process of both the soft and hard tissue components of the postextraction socket around immediately loaded dental implants after tooth extraction in maxillary esthetic areas. Materials and Methods: Subjects underwent immediate placement of single implants in postextraction sockets without bone grafting, and their immediate provisionalization with custom tooth-like interim crowns were fabricated using digital diagnostic impressions and a dental milling machine. Intraoperative and 1-year follow-up layered scans of the postextraction sockets after implantation were acquired using a 3D optical system. In the short term, subjects underwent computed tomographic scans. Digital impressions for gingival contours, originally stored as STL (standard tessellation language) files, were converted to DICOM (Digital Imaging and Communications in Medicine) files with the implant shoulder working as a referral point, which were then superimposed to 3D radiologic images. The observed volumetric and linear outcomes were measured using a program known as DentaScan. The width of the alveolar crest at the level of the implant shoulder and marginal bone levels were acquired. Nonparametric tests were applied with a level of significance set at P < .01. Results: No failure was reported after a follow-up of 1 year. Little or no inflammation of the treated areas was registered, and there were practically no signs of suppuration. The areas showed a significant reduction in the overall volumes for both soft and bone tissue, with a P value < .0001 from the baseline (0.983 ± 0.172 cm3) to the 1-year survey (0.865 ± 0.156 cm3). If the soft and bone tissue changes were separately evaluated, a significant loss (with a P value < .0001) was registered for only the bone tissues (from 0.434 ± 0.075 to 0.355 ± 0.061 cm3). Moreover, changes in gingival tissue from baseline to the 1-year survey (-0.040 ± 0.067) appeared to be significantly different from the overall volume loss (-0.118 ± 0.083 cm3). A shrinkage in width (-0.5 ± 0.7 mm) was found from baseline (12.6 ± 0.6 mm) to the 1-year followup (12.1 ± 0.9 mm). Marginal bone levels were 0.97 ± 0.70 mm and 0.39 ± 0.78 mm, respectively, at the mesial and distal aspects of the implants. Conclusions: The present analysis suggested that immediately customized provisionalization was effective enough to prevent both volume loss and linear shrinkage at the layers of the treated areas. Moreover, the buccal aspects seemed to be the areas most affected by the loss of volume. The mean loss in width, which amounted to roughly 0.5 mm, appeared to be negligible when compared to the overall width measured before surgery. [ABSTRACT FROM AUTHOR]

Poor bone quality is a major factor in skeletal fragility in elderly individuals. The molecular mechanisms that establish and maintain bone quality, independent of bone mass, are unknown but are thought to be primarily determined by osteocytes. We hypothesize that the age-related decline in bone quality results from the suppression of osteocyte perilacunar/canalicular remodeling (PLR), which maintains bone material properties. We examined bones from young and aged mice with osteocyte-intrinsic repression of TGFβ signaling (TβRIIocy-/-) that suppresses PLR. The control aged bone displayed decreased TGFβ signaling and PLR, but aging did not worsen the existing PLR suppression in male TβRIIocy-/- bone. This relationship impacted the behavior of collagen material at the nanoscale and tissue scale in macromechanical tests. The effects of age on bone mass, density, and mineral material behavior were independent of osteocytic TGFβ. We determined that the decline in bone quality with age arises from the loss of osteocyte function and the loss of TGFβ-dependent maintenance of collagen integrity.

Osteocytes locally remodel their surrounding tissue through perilacunar canalicular remodeling (PLR). During lactation, osteocytes remove minerals to satisfy the metabolic demand, resulting in increased lacunar volume, quantifiable with synchrotron X-ray radiation micro-tomography (SRµCT). Although the effects of lactation on PLR are well-studied, it remains unclear whether PLR occurs uniformly throughout the bone and what mechanisms prevent PLR from undermining bone quality. We used SRµCT imaging to conduct an in-depth spatial analysis of the impact of lactation and osteocyte-intrinsic MMP13 deletion on PLR in murine bone. We found larger lacunae undergoing PLR are located near canals in the mid-cortex or endosteum. We show lactation-induced hypomineralization occurs 14 µm away from lacunar edges, past a hypermineralized barrier. Our findings reveal that osteocyte-intrinsic MMP13 is crucial for lactation-induced PLR near lacunae in the mid-cortex but not for whole-bone resorption. This research highlights the spatial control of PLR on mineral distribution during lactation.

BACKGROUND: Several studies have found that the total flavonoids of rhizome drynariae can promote neovascularization in the induced membrane, improve the biological properties of the induced membrane, and accelerate bone remodeling in the induced membrane, but the related molecular mechanisms still need to be further explored. OBJECTIVE: To explore the effect of total flavonoids of rhizome drynariae on bone remodeling in rat femoral Masquelet-induced membrane model by regulating H-type blood vessels. METHODS: Thirty-six male Sprague-Dawley rats were stratified by body mass and then randomly divided into blank group, model group and traditional Chinese medicine group, with 12 rats in each group. A 4-mm femoral bone defect model was established in all the rats. Bone defects in the model group and traditional Chinese medicine group were filled with polymethylmethacrylate bone cement. At 6 weeks after modeling, the tail bone of the rats was implanted in the blank group, as well as in the other two groups after removal of bone cement. The traditional Chinese medicine group was given 157.5 mg/kg per day of total flavonoids of rhizome drynariae at 3 days after bone implantation, while the model and blank groups were given the same amount of saline by gavage until the 8th week after bone implantation. Bone graft samples were taken for relevant testing at 8 weeks after implantation. RESULTS AND CONCLUSION: X-ray films showed that in the blank group, the fracture line in the defect area was clear, and only a small amount of bone callus formed; in the model group, the bone defect area still existed, where discontinuous cortical bone was visible; in the traditional Chinese medicine group, the defect area was filled with newborn bone tissues, the bone marrow cavity and part of the cortical bone formed, and the fracture line disappeared. Micro-CT scans showed that the amount of new bone in the defect area was low in the blank group, the number of bone trabeculae in the defect area was significantly increased in the model group, and a large amount of new bone tissue was filled in the bone defect area in the traditional Chinese medicine group. Hematoxylin-eosin staining results showed that in the blank group, only a small amount of new bone formed in the defect area and the quality of osteogenesis was poor; in the model group, there was more new bone tissue in the defect area, but some fibrous connective tissues were interspersed within the bone tissue; and in the traditional Chinese medicine group, a large amount of new bone formed in the defect area and the quality of osteogenesis was the best. CD31/Emcn immunofluorescence double-labeling staining results showed that the number of H-type blood vessels in the newborn bone tissue in the bone defect area of the blank group was sparse and sparsely distributed; compared with the blank group, there were more H-type blood vessels in the bone tissue in the bone defect area of the model group, and the blood vessels were distributed in relatively regular strips; the number of H-type blood vessels in the bone defect area of the traditional Chinese medicine group was the highest and the blood vessels were densely distributed. To conclude, the total flavonoids of rhizoma drynariae can upregulate the expression of H-type blood vessels to enhance the angiogenic-osteogenic effect, improve the osteogenic efficiency of the rat femoral Masquelet induced membrane model, and promote bone remodeling. [ABSTRACT FROM AUTHOR]

Background: The interplay between breast cancer treatment and osteoporosis has important consequences for anticancer therapy and patient bone health. Many breast cancer therapies involve hormonal treatments that lower estrogen levels, which can lead to an increased risk of osteoporosis due to reduced bone mineral density. Aromatase inhibitors, chemotherapy, and surgeries such as oophorectomy can further aggravate bone loss, highlighting the necessity of prioritizing bone health during cancer treatment. Objective: This review is aimed at investigating the complex relationship between breast cancer therapies and bone health by examining the molecular and cellular mechanisms through which anticancer treatments lead to bone loss. It also seeks to assess the effects of various treatment options, such as selective estrogen receptor modulators (SERMs) and bisphosphonates, on reducing bone loss and maintaining bone health during cancer therapy. Method: The review explores the mechanisms underlying bone loss in breast cancer patients undergoing treatment, focusing on factors such as estrogen depletion, inflammatory cytokines, and changes in bone remodelling processes. Additionally, it evaluates the efficacy of different therapeutic interventions, including pharmacological treatments like bisphosphonates and third‐generation SERMs, in mitigating bone‐related side effects. Results: The findings indicate a critical need to balance the effectiveness of breast cancer treatments with the preservation of bone health. Pharmacological treatments like bisphosphonates and denosumab have been identified as essential for managing bone health in breast cancer patients. Furthermore, third‐generation SERMs show potential in reducing bone loss associated with cancer therapy. [ABSTRACT FROM AUTHOR]

Background: With increasing age, the social and economic burdens of postmenopausal osteoporosis are steadily increasing. This study aimed to investigate the factors that influence the development of postmenopausal osteoporosis. Methods: Postmenopausal women at the Affiliated Hospital of Jiangnan University from January 2023 to December 2023 were recruited for BMD examination. The patients were divided into a normal group, an osteopenia group and an osteoporosis group according to their T value. Questionnaires, including the Gastrointestinal Symptom Rating Scale and Short Form 12, were administered through face-to-face interviews. Bone turnover markers and serum protein levels of Fasting venous blood were detected. Results: A total of 222 postmenopausal women met the inclusion criteria were recruited. Univariate analysis revealed statistically significant differences in age, education, BMI, supplementation with soy products, supplementation with dairy products, supplementation with other nutritional supplements, exercise frequency, gastrointestinal symptom score, quality of life, 25(OH)D, total protein, albumin and prealbumin among the three groups (P < 0.05). Pearson correlation analysis revealed that gastrointestinal symptoms (r = -0.518, P < 0.01) was negatively correlated with BMD in postmenopausal women, while PCS (r = 0.194, P = 0.004), MCS (r = 0.305, P < 0.01), 25(OH)D (r = 0.531, P < 0.01), total protein (r = 0.324, P < 0.01), albumin (r = 0.341, P < 0.01) and prealbumin (r = 0.259, P < 0.01) were positively correlated with BMD. Logistic regression analysis revealed that both the gastrointestinal symptom score and serum 25(OH)D level were found to have a significant association with BMD (both P < 0.01). This association remained significant even after adjusting for age, BMI, education level, dietary habits, and exercise frequency. Conclusion: Gastrointestinal symptoms and serum 25(OH)D elevel are associated with increased risk of osteoporosis in postmenopausal women and may be useful in predicting osteoporosis in postmenopausal women. [ABSTRACT FROM AUTHOR]

Background: Adult growth hormone deficiency (AGHD) is associated with an increased risk of fractures and impaired bone microstructure. Understanding the metabolic changes accompanying bone deterioration in AGHD might provide insights into mechanisms behind molecular changes and develop new biomarkers or nutritional strategies for bone destruction. Our study aimed to investigate the association between altered metabolite patterns and impaired bone microstructure in adult rats with growth hormone deficiency. Methods: Thirty seven-week-aged adult Lewis dwarf homozygous (dw/dw) rats (five females and five males), and adult Lewis dwarf heterozygous (dw/ +) rats (five females and five males) rats were compared. Micro-computed tomography (Micro-CT) was used to examine the bone's microstructure. Hematoxylin and eosin (H&E) staining were used to quantify the histological characteristics. Liquid chromatography-mass spectrometry untargeted serum metabolomic analysis was applied in the study. ELISA was used to measure serum bone turnover markers and IGF-1 levels. Results: Adult dw/dw rats exhibited great reductions in trabecular volume bone density (Tb.vBMD), bone volume/total volume (BV/TV), and cortical thickness (Ct. Th) compared with adult dw/ + rats (all p values < 0.05), indicating significant impairment in bone microstructure. The serum metabolite profiles revealed substantial differences between the dw/dw rats and dw/ + rats. A total of 134 differential metabolites in positive ion mode and 49 differential metabolites in negative mode were identified. Five metabolites, including Lysophosphatidylcholine(LPC) 20:3, LPC22:6, LPC22:4, cortisol and histamine levels were upregulated in dw/dw rats. The steroid hormone biosynthesis and bile secretion pathways were the main perturbed metabolic pathways. There were significant associations between differential metabolites and the impaired bone microstructure parameters, indicating that the selected metabolites might serve as potential biomarkers for deteriorated bone microstructure in AGHD. Conclusion: Adult dw/dw rats exhibit impaired bone microstructure and distinct serum metabolic profiles, and the altered metabolites were significantly associated with bone microstructure destruction. This provides a new insight into understanding the mechanism of bone deterioration in AGHD patients from a metabolic perspective. [ABSTRACT FROM AUTHOR]

Medication-related osteonecrosis of the jaw is a rare but severe complication with challenging treatment protocols. Cold atmospheric plasma (CAP) has shown promising effects in wound healing, cell proliferation and viability. This study investigated the effect of CAP on osteoblasts in a culture medium containing bisphosphonates. Pilot study was designed to determine the optimal setting of CAP. MG-63 cells were exposed to zoledronic acid at a concentration of 10 micromolar for 72 h. Study groups with the best MTT assay results, were chosen for assessing OPG and RANKL genes by RT-PCR. Cell viability was significantly higher in groups 9 kV.1 mm.90 s, 10 kV.1 mm.60 s, and 12 kV.1 mm.60 s (P < 0.05). Expression of RANKL in these groups was significantly lower than the positive control group (medium culture without zoledronic and plasma treatment) and higher than the BP group (culture with zoledronic without plasma treatment), except for the 12 kV.1 mm.60 s group, which did not differ significantly from the positive control group (P > 0.05). OPG decreased in all test groups compared to BP (p < 0.05), except for the 12 kV.1 mm.60 s group, which did not significantly differ from BP (P > 0.05). RANKL/OPG ratio in groups 9 kV.1 mm.90 s and 12 kV.1 mm.60 s significantly increased compared to BP (P < 0.05).CAP treatment may enhance the viability of osteoblasts exposed to bisphosphonates, increase their activity levels, enhance osteoclast activity, and improve bone turnover rates. [ABSTRACT FROM AUTHOR]

Bone loss in the alveolar ridge is a factor widely studied by dentists in implant surgeries, as it poses a major challenge for aesthetic and functional recovery in patients with large maxillary bone defects. Synthetic biomaterials function as grafts designed to replace and remodel bone tissue. Calcium phosphate is a biomaterial that has good properties such as biocompatibility and bioactivity, making it a reference in bone replacement treatments. A synthetic biomaterial such as calcium phosphate can be obtained by various synthesis techniques. The microwave hydrothermal method (HTMO) is a pathway that allows changes in synthesis parameters and significantly increases the transmission efficiency of materials such as synthetic calcium phosphate derivatives. The study proposes obtaining a biomaterial for bone grafting based on calcium phosphate by the microwave HTMO and evaluating its microstructural and physicochemical characteristics. The parameters tested in this process were temperature and reaction time. The calcium phosphate particulates were obtained by the microwave HTMO at temperatures of 110°C and 130°C for 60 min and calcined at 300°C, 500°C, and 700°C. Microstructural and physicochemical characterization analyses were carried out using scanning electron microscopy, Fourier transform infrared, and X‐ray diffraction. The results obtained showed the presence of more than one calcium phosphate biological interest phase, as hydroxyapatite (HA), tricalcium phosphate (β‐TCP), and octacalcium phosphate (OCP), highlighting with increasing calcination temperature, the β‐TCP phase becomes evident. The proposed synthesis method was efficient in obtaining a biomaterial with suitable physical and chemical characteristics, with an association of crystalline phases of biological interest related to the increase in synthesis temperature and calcination temperature. [ABSTRACT FROM AUTHOR]

AbstractBackgroundMethodsResultsConclusionThe aberrant H-type vessel formation was found to be intimately linked to subchondral bone remodeling during osteoarthritis (OA) development. Herein, we investigated the role and mechanism of osteoblast-secreted slit guidance ligand 3 (Slit3) in H-type vessel formation during OA progression.Slit3 protein levels in subchondral bone samples of OA patients were detected. The isolated osteoblasts were transfected with Slit3 overexpression or knockdown plasmids, and their conditioned medium was cultured with endothelial progenitor cells (EPCs). The migration, tube formation, VEGF, and H-type vessel marker protein CD31 and endomucin (EMCN) levels in EPCs were accessed. The interactions between Slit3 and roundabout (Robo) family members were validated by Co-IP assay. Besides, whether the Slit3/Robo signaling affects the transforming growth factor β1 (TGF-β1)/SMADs pathway was determined. Additionally, sh-Slit3 was injected into OA mice, followed by the detection of articular cartilage degradation, subchondral bone remodeling, and H-type vessel formation.Slit3 was upregulated in subchondral bone tissues of OA patients. Slit3 overexpression in osteoblasts intensified the migration and H-type vessel formation of EPCs, while Slit3 knockdown showed the opposite results. Slit3 overexpression enhanced Robo1 protein level. Robo1 knockdown abrogated Slit3-mediated migration and H-type vessel formation in EPCs. Slit3 activated the TGF-β1/SMADs pathway in EPCs, which might be associated with H-type vessel formation in EPCs. Additionally, Slit3 silencing restrained articular cartilage degradation, aberrant subchondral bone formation, and H-type vessel formation in OA mice.Inhibition of Slit3/Robo1 signaling alleviates osteoarthritis in mice by reducing abnormal H-type vessel formation in the subchondral bone. [ABSTRACT FROM AUTHOR]

Osteoporosis becomes a global public health concern due to its rising prevalence and substantial impact on life quality. Salvia miltiorrhiza Bunge (Salviae Miltiorrhizae Radix et Rhizoma, SM) has been firstly recorded in Shen Nong's Herbal Classic, and is frequently prescribed in conjunction with other herbs for the management of osteoporosis. This systematic review aims to comprehensively analyze the recent advances of SM on osteoporosis in traditional Chinese clinical uses and preclinical investigations. Literature encompassing pertinent studies were systematically retrieved across multiple databases, including the PubMed, Web of Science, Chinese National Knowledge Infrastructure, Chinese VIP Database, and Chinese Biomedical Literature Database. Original investigations spanning from February 2014 to March 2024, including traditional Chinese medicine (TCM) clinical trials and preclinical studies, were employed to analyze the effects and actions of SM on osteoporosis. Thirty-eight TCM clinical trials were identified to employ SM in combination with other herbs for the management of primary and secondary osteoporosis. The overall efficacy was between 77% and 96.67%. Forty preclinical studies were identified to investigate the effects and actions of SM and/or its ingredients on osteoporosis. The anti-osteoporosis actions of this herb may be attributed to inhibit osteoclastogenesis/bone resorption and promote osteoblastogenesis/osteogenesis. The ethanol extracts and its ingredients (tanshinones) inhibit osteoclastogenesis/bone resorption by inhibiting the MAPK/NF-κB/NFATc1 signaling pathway and cathepsin K-induced collagen degradation. Both ethanol extracts (tanshinones) and water extracts (Sal B and tanshinol) contribute to osteoblastogenesis by promoting osteogenesis and angiogenesis via activation of the Wnt/β-catenin/VEGF and ERK/TAZ pathways, and eliminating ROS production targeting Nrf2/ARE/HO-1 pathway. In conclusions, SM may offer a novel strategy for osteoporosis management. Well-designed clinical trials are still needed to evaluate the actions of this herb and its ingredients on bone remodeling. [ABSTRACT FROM AUTHOR]

Background: The incidence of osteoarthritis (OA) is increasing, yet its pathogenesis remains largely unknown. Recent studies suggest that abnormal subchondral bone remodeling plays a crucial role in OA development, highlighting a gap in clinical treatments targeting this aspect. Soybean Isoflavone (SI) has shown potential in treating OA, although its mechanisms are not fully understood. Methods: This research investigated the effects of SI on subchondral bone remodeling in an OA rat model, assessing joint damage, OARSI scores, and type H vessel formation (CD31hiEmcnhi expression). Additionally, the expression of ALP, OCN, BMP, and TSC1 was evaluated to determine involvement of the mTORC1 pathway. In vitro studies on IL-1β-induced osteoblasts further examined the impact of SI on TSC1/mTORC1 signaling and related markers. Results: SI treatment reduced joint damage and OARSI scores in the rat OA model, significantly decreasing CD31hiEmcnhi expression, indicating a reduction in type H vessel formation. SI also downregulated ALP, OCN, and BMP expression while upregulating TSC1, suggesting inhibition of the mTORC1 signaling pathway and VEGF release. In vitro, SI increased TSC1 expression and decreased mTORC1 signaling, VEGF, ALP, OCN, and BMP levels in IL-1β-induced osteoblasts. Conclusion: SI targets the TSC1/mTORC1 signaling pathway to suppress osteoblast activation and VEGF release, inhibiting type H vessel formation and slowing abnormal subchondral bone remodeling. These findings provide a novel therapeutic approach for OA by focusing on subchondral bone remodeling mechanisms. [ABSTRACT FROM AUTHOR]

Background: The rarity and variability of MEN1-related primary hyperparathyroidism (mPHPT) has led to contradictory data regarding the bone phenotype in this patient population. Methods: A single-center retrospective study was conducted among young age- and sex-matched patients with mPHPT and sporadic hyperparathyroidism (sPHPT). The main parameters of calcium–phosphorus metabolism, bone remodeling markers, and bone mineral density (BMD) measurements were obtained during the active phase of hyperparathyroidism before parathyroidectomy (PTE) and 1 year after. Trabecular Bone Score (TBS) and 3D-DXA analysis of the proximal femur were used to evaluate the differences in bone architecture disruption between groups. Results: Patients with mPHPT had significant lower preoperative BMD compared to sPHPT at lumbar spine—LS (p = 0.002); femur neck—FN (p = 0.001); and total hip—TH (p = 0.002). 3D-DXA analysis showed the prevalence of cortical rather than trabecular bone damage in mPHPT compared to sPHPT: cortical thickness (p < 0.001); cortical surface BMD (p = 0.001); cortical volumetric BMD (p = 0.007); and trabecular volumetric BMD (p = 0.029). One year after, PTE DXA and 3D-DXA parameters were similar between groups, while 3D-visualisation showed more extensive regeneration in cortical sBMD and cortical thickness in mPHPT. Conclusions: mPHPT is associated with lower preoperative BMD values with predominant architecture disruption in the cortical bone. The absence of differences in DXA and 3D-DXA parameters 1 year after PTE between mPHPT/sPHPT combined with significantly lower BMD in mPHPT at the initial stage may indicate faster bone recovery after surgery in mPHPT than in sPHPT. [ABSTRACT FROM AUTHOR]

Asymptomatic primary hyperparathyroidism (PHPT) involves 80–90% of the parathyroid tumor-associated cases of PHPT in the modern medical era, while normocalcemic PHPT (NPHPT) has a prevalence of 0.1–11%. We aimed to analyze the bone status and mineral metabolism in NPHPT amid conservative or surgical management. In this narrative review, we searched PubMed (between January 2020 and July 2024) via different keywords. Fourteen studies from the final analysis (388 patients with NPHPT; 1188 with PHPT; and 803 controls) showed that mean serum calcium levels varied between 2.57 and 2.26 mmol/L in NPHPT. Ten studies identified a similar 24 h urinary calcium in NPHPT versus hypercalcemic PHPT (HPHPT). Except for one study, a mandatory vitamin D analysis was performed, but the 25-hydroxyvitamin D cut-offs varied. Osteoporosis (n = 6 studies; N = 172 with NPHPT) was confirmed in 41.7–100% of NPHPT subjects. In surgery candidates, this rate might be overestimated. A DXA analysis was performed in eight studies (235 subjects with NPHPT, and 455 patients with HPHPT); two studies identified a lower BMD in HPHPT < NPHPT, but the results were not homogenous. A single study analyzed the TBS and found similar results in NPHPT. The prevalence of fractures (n = 9) varied between 7.4% and 42.8% in NPHPT. Bone turnover markers (N = 262 patients, n = 8 studies) showed lower bone formation markers in NPHPT versus PHPT (n = 3). Two studies analyzed the BMD and bone turnover markers following parathyroidectomy (161 patients, including 30 patients with NPHPT; mean ages over 60 years). To conclude, given the wide spectrum of complications associated with PHPT, an early diagnosis and proper management is essential. A more extensive screening in patients with osteoporosis and kidney stones might lead to the discovery of NPHPT, a more recently described form of PHPT. While it is still unclear whether NPHPT is an early stage of HPHPT or a separate entity, recent findings show similar osteoporosis and fracture occurrence, and an improvement in bone metabolism, following parathyroidectomy. More extensive prospective studies are crucial to understand the natural course of the disease, to reach a consensus regarding parathyroidectomy indications and surgery candidates' selection, and to ensure proper personalized management for these patients. With the evolving diagnosis methods, PHPT has become a condition with a changing clinical presentation, which now requires modern evaluation and treatment approaches. [ABSTRACT FROM AUTHOR]

Glycogen storage disease (GSD) is the most prevalent inherited disorder of glycogen metabolism for which no causal treatment is available. In recent years, thanks to the improved clinical management, the life expectancy of these patients extended, disclosing previously unidentified adverse conditions in other organs. In this study, we evaluated the clinical bone complications and the cellular responses in 20 patients (aged 14.1 ± 3.4 years) affected by GSD type I. Fragility fractures were reported in 35% of the patients, which were older than unfractured patients. They involved appendicular skeletal segments, while no vertebral deformity was detected. 60% of the patients had a bone mineral density (BMD) "below the expected range for age", and lumbar spine (LS) BMD Z-scores positively correlated with muscle strength. Circulating mineral and bone markers showed reduction in the older subjects, with no increase in the pubertal age. Significant correlations could not be detected between circulating markers and LS BMD Z-scores, except for sclerostin levels, which also correlated with muscle strength. The osteoclasts differentiated from patients' peripheral blood mononuclear cells did not show cell-autonomous alterations. However, circulating osteoclast precursors from healthy individuals cultured in the presence of patients' sera exhibited increased osteoclastogenesis compared to control sera suggesting that GSD type I serum factors could affect osteoclast function in a non-autonomous manner. In contrast, circulating osteoprogenitors were unremarkable. [ABSTRACT FROM AUTHOR]

In conversations about bone loss and the importance of calcium homeostasis, patients frequently inquire about the association with arterial calcifications. Although a relationship between bone loss and the occurrence of vascular calcifications is suspected, it is not yet fully investigated and understood. This study aims to analyze associations between bone mineralization, structure, and vascular calcification at the lower leg in patients with low bone mineral density in HR-pQCT. We retrospectively analyzed 774 high-resolution quantitative computed tomography (HR-pQCT) scans of the distal tibia for the presence of vascular calcifications. After sex-specific propensity score matching for age and BMI to account for confounders, 132 patients remained for quantification of bone microstructure, bone density, lower leg arterial calcification (LLAC), and laboratory parameters of bone turnover. The interactions between bone parameters and vascular calcification were quantified by regression analyses. The calcium metabolism was not different between individuals with and without LLAC, nor oral calcium supplementation. Female patients with LLAC had a higher cortical perimeter (p = 0.016) compared to female patients without LLAC, whereas male patients with LLAC had lower cortical pore diameter than male patients without LLAC (p = 0.027). The appearance of LLAC was sex specifically associated with bone parameters. In female patients, only plaque density was associated with HR-pQCT bone parameters and age, whereas in male patients, plaque volume was associated with HR-pQCT parameters of the distal tibia. Female patients exhibit an increasing plaque density depended on age and trabecular thinning. Decreasing cortical pore diameter and trabecular number along with increasing bone mineralization are linked to increasing plaque volume in male patients. [ABSTRACT FROM AUTHOR]

Transgender and gender diverse individuals experience a gender identity that differs from the sex assigned at birth. Some transgender men may request testosterone to induce virilization; however, its impact on bone health remains to be fully elucidated. The objective of this systematic review and meta-analysis was to evaluate the modifications in bone metabolism over a short-term period among transgender men initiating testosterone therapy. A systematic search was conducted in PubMed, Scopus, Web of Science, and Cochrane Library. The articles of interest had to report longitudinal evaluation conducted among transgender men, before starting testosterone and after 12 and 24 months of therapy. The analyzed parameters were BMD, calcium, phosphate, 25OHD, PTH, P1NP, BAP, osteocalcin and CTx. Mean differences with 95% coefficient intervals were combined using random effects models. Funnel plot, Egger's test, and trim-and-fill analysis were used to assess publication bias. Fourteen studies met the inclusion criteria, including 1484 subjects. In absence of heterogeneity, BMD did not significantly change at lumbar spine, hip, femoral neck, and whole-body evaluations. Calcium, phosphate, 25OHD and PTH remained stable over time. Regarding bone turnover markers, only P1NP showed a statistically significant increase after 12 months of T therapy, in absence of heterogeneity (SMD 0.61 mcg/l; 95% CI: 0.40–0.83; p < 0.0001; I2 = 0%, Pforheterogeneity = 0.48). Testosterone therapy among transgender men seems not to disrupt bone health after 12 and 24 months. A statistically significant elevation in P1NP levels after 12 months of therapy may indicate a positive anabolic effect of testosterone in the short-term. [ABSTRACT FROM AUTHOR]

The incidence of osteoporosis and related fractures increases significantly with age, impacting public health and associated costs. Postmenopausal osteoporosis results from increased bone resorption due to decreased estrogen levels. The endocannabinoid system, especially cannabidiol (CBD), has shown therapeutic potential in modulating bone formation. This study investigated the effects of administration of CBD in rats after the onset of with ovariectomy-induced osteopenia (OVX). Forty-eight female Sprague‒Dawley rats were divided into four groups (n = 12): OVX + CBD, SHAM + CBD, OVX + vehicle, and SHAM + vehicle. CBD was administered intraperitoneally for 3 weeks. After euthanasia, the bone quality, mechanical properties, and bone microarchitecture of the femurs and lumbar vertebrae were assessed by microcomputed tomography (micro-CT), bone densitometry, mechanical tests, and histological and immunohistochemical analyses. CBD treatment improved the bone mineral density (BMD) of the lumbar vertebrae and increased the BV/TV% and Tb.N in the femoral neck. There were also improvements in the mechanical properties, such as the maximum force and stiffness of the femurs and vertebrae. CBD significantly increased the bone matrix in osteopenic femurs and vertebrae, Although did not significantly influence the expression of RANKL and OPG, in ovariectomized animals, there was an increase in osteoblasts and a decrease in osteoclasts. Determining the optimal timing for CBD use in relation to postovariectomy bone loss remains a crucial issue. Understanding when and how CBD can be most effective in preventing or treating bone loss is essential to emphasize the importance of early diagnosis and treatment of osteoporosis. However, further studies are needed to explore in more detail the efficacy and safety of CBD in the treatment of postmenopausal osteoporosis. [ABSTRACT FROM AUTHOR]

Aim: To assess the possibility of vertical alveolar ridge augmentation by means of activation of the periosteum. Materials and Methods: Six adult male Beagle dogs were used for the study. All premolars and first molars were extracted, and one vertical saucer‐shaped bony defect was created on each side of the mandible. After 3 months of healing, full‐thickness muco‐periosteal flaps were elevated, and one distraction device was placed on each side of the mandible. The distraction plate was left submerged, and the activation mechanism connected to the distraction rod was exposed intra‐orally. The protocol of periosteal activation (PP: periosteal 'pumping') was initiated after a latency of 7 days. The alternation of activation and relaxation at the rate of 0.35 mm/12 h during 5 days was followed by the sole activation of 0.35 mm/12 h for 5 days (PP group). Devices were left inactivated on the contralateral control side of the mandible (C group). All animals were euthanized after 8 weeks of consolidation. Samples were analysed histologically and by means of micro‐CT. Results: New mature lamellar bone was formed over the pristine bone in all groups. More intensive signs of bone modelling and remodelling were observed in the PP group compared to the C group. Mean new bone, bone marrow, connective tissue and total volumetric densities were greater in the PP group (p < 0.001, p = 0.001, p = 0.003 and p < 0.001, respectively). No differences were observed in the relative area parameters. Total tissue volume and bone volume were higher in the PP group (p = 0.031 and p = 0.076, respectively), while the bone mineral densities were higher in the C group (p = 0.041 and p = 0.003, respectively). Trabecular number, trabecular thickness and trabecular separation values were similar between the two groups. Conclusions: Regeneration of vertical alveolar bone ridge defects may be enhanced by activation of the periosteum, without the application of bone grafting materials. [ABSTRACT FROM AUTHOR]

In this paper, the bone tissue was modeled as a linear viscoelastic material saturated with interstitial fluid. We considered a specific case of harmonic loading and related the mechanical stimuli to the loading frequency. In this way, we could include the inertial effect in the model while not having to deal with the perturbation during each loading period. Two types of mechanical signals were considered: strain energy and dissipation energy. A parametric study revealed the dependency of the two signals on loading frequency and material property. The evolution of the apparent mass density supported the parametric study's findings. Under the three different frequency loadings, the strain energy-stimulated samples experienced identical remodeling scenarios. The samples stimulated with dissipation energy, on the other hand, exhibited a strong frequency dependence. An additional study was performed to investigate the effect of long-term variations in the loading frequency on the remodeling process. This demonstrated the model's capabilities in designing and evaluating load regimes for rehabilitation following a bone injury or bone reconstruction. [ABSTRACT FROM AUTHOR]

Preclinical models of osteochondral defects (OCDs) are fundamental test beds to evaluate treatment modalities before clinical translation. To increase the rigor and reproducibility of translational science for a robust "go or no‐go," we evaluated disease progression and pain phenotypes within the whole joint for two OCD rat models with same defect size (1.5 x 0.8 mm) placed either in the trochlea or medial condyle of femur. Remarkably, we only found subtle transitory changes to gaits of rats with trochlear defect without any discernible effect to allodynia. At 8‐weeks post‐surgery, anatomical evaluations of joint showed early signs of osteoarthritis with EPIC‐microCT. For the trochlear defect, cartilage attenuation was increased in trochlear, medial, and lateral compartments of the femur. For condylar defect, increased cartilage attenuation was isolated to the medial condyle of the femur. Further, the medial ossicle showed signs of deterioration as indicated with decreased bone mineral density and increased bone surface area to volume ratio. Thus, OCD in a weight‐bearing region of the femur gave rise to more advanced osteoarthritis phenotype within a unilateral joint compartment. Subchondral bone remodeling was evident in both models without any indication of closure of the articular cartilage surface. We conclude that rat OCD, placed in the trochlear or condylar region of the femur, leads to differing severity of osteoarthritis progression. As found herein, repair of the defect with fibrous tissue and subchondral bone is insufficient to alleviate onset of osteoarthritis. Future therapies using rat OCD model should address joint osteoarthritis in addition to repair itself. [ABSTRACT FROM AUTHOR]

Preventing the decrease in bone mineral density (BMD) is significant for postmenopausal women. We previously discovered that rhamnose, a deoxy monosaccharide used as a food additive, could suppress bone resorption; however, studies confirming this effect in postmenopausal women are lacking. Therefore, this pilot study aimed to explore whether rhamnose could help maintain BMD via bone resorption suppression in postmenopausal women. The participants consumed either 1.0 or 0.5 g/day of rhamnose or placebo for 24 weeks, and BMD (lumbar spine and femur) and bone turnover markers were measured. After 24 weeks, the group consuming rhamnose 1.0 g/day exhibited a significantly higher BMD of the lumbar spine than the placebo group. Furthermore, the levels of tartrate-resistant acid phosphatase 5b, a bone resorption marker, were significantly lower in both rhamnose groups. These results indicated that rhamnose might contribute to the maintenance of BMD by suppressing bone resorption in healthy postmenopausal women (UMIN000046570). [ABSTRACT FROM AUTHOR]

Basic, translational and clinical research over the past few decades has provided new understanding on the mechanisms by which activation of the receptor of parathyroid hormone (parathyroid hormone 1 receptor (PTH1R)) regulates bone physiology and pathophysiology. A fundamental change in the field emerged upon the recognition that osteocytes, which are permanent residents of bone and the most abundant cells in bone, are targets of the actions of natural and synthetic ligands of PTH1R (parathyroid hormone and abaloparatide, respectively), and that these cells drive essential actions related to bone remodelling. Among the numerous genes regulated by PTH1R in osteocytes, SOST (which encodes sclerostin, the WNT signalling antagonist and inhibitor of bone formation) has a critical role in bone homeostasis and changes in its expression are associated with several bone pathologies. The bone fragility syndrome induced by diabetes mellitus is accompanied by increased osteocyte apoptosis and changes in the expression of osteocytic genes, including SOST. This Review will discuss advances in our knowledge of the role of osteocytes in PTH1R signalling and the new opportunities to restore bone health in diabetes mellitus by targeting the osteocytic PTH1R–sclerostin axis. This article reviews the role of the parathyroid hormone 1 receptor (PTH1R) pathway in bone homeostasis and of osteocytes as mechanosensors and drivers of bone remodelling. It will also discuss how the PTH1R–sclerostin axis can be harnessed for the treatment of bone disease induced by diabetes mellitus. Key points: Natural and synthetic ligands of the parathyroid hormone 1 receptor (PTH1R) profoundly regulate bone formation and resorption by activating downstream signalling in cells of the osteoblastic lineage. Osteocytes are critical target cells of parathyroid hormone (PTH) action in bone; activation of osteocytic PTH1R is sufficient to stimulate bone remodelling, whereas its deletion impairs PTH-induced bone anabolism. Osteocytes, the most abundant bone cells and terminally differentiated cells of the osteoblastic lineage, drive bone remodelling in response to mechanical and hormonal cues under physiological and pathological conditions. The bone fragility syndrome induced by diabetes mellitus is accompanied by increased osteocyte apoptosis and changes in the expression of osteocytic genes, including SOST (which encodes sclerostin, the WNT signalling antagonist and inhibitor of bone formation). Targeting osteocyte-derived molecules and osteocytic signalling pathways represents a paradigm shift in the treatment of bone diseases, including osteoporosis due to ageing, glucocorticoids, certain cancers and diabetes mellitus. Bone anabolism activated by ligands of PTH1R or by direct neutralization of sclerostin reverses the diabetic bone signature at the tissue, cellular and molecular levels. [ABSTRACT FROM AUTHOR]

Some previous researches have demonstrated that appropriate mechanical stimulation can enhance bone formation. However, most studies have employed the strain energy density (SED) method for predicting bone remodeling, with only a few considering the potential impact of wall fluid shear stress (FSS) on this process. To bridge this gap, the current study compared the prediction of bone formation and resorption via SED and wall FSS by using fluid-solid coupling numerical simulation. Specifically, 8-week-old female Sprague–Dawley rats were subjected to stretching of the eighth caudal vertebra using a custom-made device. Based on micro-computed tomography images, a three-dimensional model integrating fluid–solid coupling was created to represent compact bone, cancellous bone, and bone marrow. The animals were grouped into control, 1 Hz, and 10 Hz categories, wherein a tensile displacement load of 1000 με was applied to the loading end. The results revealed that SED values tended to increase with elevated porosity, whereas wall FSS values decreased it. Notably, wall FSS demonstrated the higher predictive accuracy for cancellous bone resorption than SED. These findings support the notion that fluid flow within cancellous bone spaces can significantly impact bone resorption. Therefore, the findings of this study contribute to a more comprehensive understanding of the role of wall FSS in bone remodeling, providing a theoretical support for the dynamic evolution of bone structures under mechanical stimulation. [ABSTRACT FROM AUTHOR]

Thalassemic osteopathy includes low bone mass and impaired bone microarchitecture. We aimed to evaluate the prevalence and determinants of bone quantity (osteoporosis) and quality (microarchitecture) in a cohort of adult patients with transfusion-dependent thalassemia (TDT). Patients with TDT (n = 63) and age- and BMI-matched controls (n = 63) were recruited in the study. Areal bone mineral density (BMD) was measured using DXA Hologic scanner. P1NP and β-CTX were estimated by electrochemiluminescence assay. Bone geometry and volumetric BMD (vBMD) were estimated by second-generation high-resolution peripheral quantitative computed tomography. Bone turnover marker β-CTX was significantly lower in the TDT group, but there was no difference in P1NP levels. Low bone mass (Z ≤ −2) was present in greater proportion of patients both at lumbar spine (LS) (54 vs 0%; p = .001) and femoral neck (FN) (33 vs 8%; p = .001). Hypogonadism was associated with low BMD at FN (OR 10.0; 95% CI, 1.2–86; p = .01) and low hemoglobin with low BMD at LS (OR 1.58; 95% CI, 0.96–2.60; p = .07). The mean trabecular bone score was also significantly lower in patients compared with controls (1.261 ± 0.072 vs 1.389 ± 0.058). Total, cortical and trabecular vBMD were significantly lower in cases than controls. The trabecular number and cortical thickness were significantly lower and trabecular separation higher in cases than controls. Adults with TDT have significantly lower areal, cortical and trabecular vBMD. The bone microarchitecture is also significantly impaired in terms of lower number and wider spacing of trabeculae as well as lower cortical thickness and area at both radius and tibia. Graphical Abstract Lay Summary: Bone quantity and quality are likely to be affected in patients with thalassemia who are dependent on regular blood transfusions. This study evaluated bone health in adults with transfusion-dependent thalassemia (TDT) by comparing bone density and microarchitecture with age- and BMI-matched controls. Adults with TDT had significantly lower bone mineral density (both areal and volumetric), suggesting low bone quantity compared to healthy controls. Trabecular and cortical microarchitecture were also adversely affected, suggesting impaired bone quality. Overall, the study highlights that adults with TDT have significantly compromised bone quantity and quality, increasing their risk for osteoporosis and related fractures. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a common joint disorder affecting about 7% of the global population, primarily characterized by the gradual loss of articular cartilage. This degeneration results from local inflammation, matrix depletion, and direct cartilage damage. A critical element in this process is the activation of the stimulator of the interferon genes (STING) pathway. Emerging evidence highlights its potential as a therapeutic target, with natural products showing promise as inhibitors. Our study centers on Acacetin, a basic unit of polyketides known for its anti-inflammatory properties. Prior research has highlighted its potential interaction with STING based on the structure. Thus, this study aimed to assess the effectiveness of Acacetin as a STING inhibitor and its protective role against OA. In vitro experiments showed that Acacetin pretreatment not only mitigated interleukin-1β (IL-1β)-induced cytotoxicity but also decreased the inflammatory response and degeneration in chondrocytes stimulated IL-1β. In vivo studies revealed that Acacetin administration significantly reduced articular cartilage destruction, abnormal bone remodeling, and osteophyte formation in a model of OA induced by destabilization of the medial meniscus (DMM). Mechanistically, Acacetin was found to interact directly with STING, and inhibit IL-1β-induced activation of STING, along with the subsequent phosphorylation of the TBK1/NF-κB pathway in chondrocytes. In conclusion, our findings establish Acacetin as an effective inhibitor of STING that protects chondrocytes from IL-1β-induced damage and slows the progression of OA in mice. [ABSTRACT FROM AUTHOR]

Background: Musculoskeletal injuries and chronic degenerative diseases pose significant challenges in equine health, impacting performance and overall wellbeing. Sex Hormone-Binding Globulin (SHBG) is a glycoprotein determining the bioavailability of sex hormones in the bloodstream, and exerting critical metabolic functions, thus impacting the homeostasis of many tissues including the bone. Methods: In this study, we investigated the potential role of SHBG in promoting osteogenesis and its underlying mechanisms in a model of equine adiposederived stromal cells (ASCs). An SHBG-knocked down model has been established using predesigned siRNA, and cells subjected to osteogenic induction medium in the presence of exogenous SHBG protein. Changes in differentiation events where then screened using various analytical methods. Results: We demonstrated that SHBG treatment enhances the expression of key osteoconductive regulators in equine ASCs CD34+ cells, suggesting its therapeutic potential for bone regeneration. Specifically, SHBG increased the cellular expression of BMP2/4, osteocalcin (OCL), alkaline phosphatase (ALP), and osteopontin (OPN), crucial factors in early osteogenesis. Furthermore, SHBG treatment maintained adequate apoptosis and enhanced autophagy during osteogenic differentiation, contributing to bone formation and remodeling. SHBG further targeted mitochondrial dynamics, and promoted the reorganization of the mitochondrial network, as well as the expression of dynamics mediators including PINK, PARKIN and MFN1, suggesting its role in adapting cells to the osteogenic milieu, with implications for osteoblast maturation and differentiation. Conclusion: Overall, our findings provide novel insights into SHBG's role in bone formation and suggest its potential therapeutic utility for bone regeneration in equine medicine. [ABSTRACT FROM AUTHOR]

Background: Gouty arthritis is a common inflammatory arthritis. The recurrent gout attacks severely damage the joint's function, lead to bone erosion, and affect bone metabolism. The role of magnesium (Mg) ions in bone homeostasis has been recognized, whereas its specific relationship with gouty bone erosion remains unclear. This study examined the association between serum ionized Mg levels and bone erosion in patients with gout arthritis. Methods: A total of 769 patients with gout arthritis were included in the study. Participants were classified into four groups based on the quartiles of the serum ionized Mg level. Logistic regression analysis assessed the association between serum ionized Mg and bone erosion. Results: Compared to patients without bone erosion, serum ionized Mg levels were lower in gout patients with bone erosion (p<0.001). When dividing serum ionized Mg into quartiles, the prevalence rate of bone erosion in group Q1, representing the patients with the lowest serum ionized Mg levels, was notably higher than in Q2, Q3, and Q4 (60.2% vs. 43.6%, 45.6%, 40.3%, p<0.001). Multiple logistic regression analysis revealed that patients in Q2-Q4 had a lower odds ratio (OR) of bone erosion compared to those in Q1 (ORs were 0.520, 0.533, and 0.411 in Q2-Q4, respectively, p<0.001). Conclusion: The incidence of bone erosion is higher in gout arthritis patients with lower serum ionized Mg levels. High serum ionized Mg levels may be an independent protective factor for bone erosion in gout arthritis. Thus, Mg supplementation may be a promising approach to prevent or slow down the development of bone erosion in gouty arthritis. [ABSTRACT FROM AUTHOR]

Osteoblasts are mainly derived from mesenchymal stem cells in the bone marrow. These stem cells can differentiate into osteoblasts, which have the functions of secreting bone matrix, promoting bone formation, and participating in bone remodeling. The abnormality of osteoblasts can cause a variety of bone-related diseases, including osteoporosis, delayed fracture healing, and skeletal deformities. In recent years, with the side effects caused by the application of PTH drugs, biphosphonate drugs, and calmodulin drugs, people have carried out more in-depth research on the mechanism of osteoblast differentiation, and are actively looking for natural compounds for the treatment of osteoporosis. The Wnt/β-catenin signaling pathway is considered to be one of the important pathways of osteoblast differentiation, and has become an important target for the treatment of osteoporosis. The Wnt/β-catenin signaling pathway, whether its activation is enhanced or its expression is weakened, will cause a variety of diseases including tumors. This review will summarize the effect of Wnt/β-catenin signaling pathway on osteoblast differentiation and the correlation between the related proteins in the pathway and human diseases. At the same time, the latest research progress of natural compounds targeting Wnt/β-catenin signaling pathway against osteoporosis is summarized. [ABSTRACT FROM AUTHOR]

Abstrct: Background: Apoptotic vesicles (ApoVs), which are extracellular vesicles released by apoptotic cells, have been reported to exhibit substantial therapeutic potential for inflammatory diseases and tissue regeneration. While extensive research has been dedicated to mesenchymal stem cells (MSCs), the investigation into immune cell-derived ApoVs remains limited, particularly regarding the function and fate of macrophage-derived ApoVs in the context of periodontitis (PD). Results: Our study corroborates the occurrence and contribution of resident macrophage apoptosis in Porphyromonas gingivalis (Pg)-associated PD. The findings unveil the pivotal role played by apoptotic macrophages and their derived ApoVs in orchestrating periodontal bone remodeling. The enrichments of diverse functional miRNAs within these ApoVs are discerned through sequencing techniques. Moreover, our study elucidates that the macrophage-derived ApoVs predominantly deliver miR-143-3p, targeting insulin-like growth factor-binding protein 5 (IGFBP5), thereby disrupting periodontal bone homeostasis. Conclusions: Our study reveals that macrophages in Pg-associated PD undergo apoptosis and generate miR-143-3p-enriched ApoVs to silence IGFBP5, resulting in the perturbation of osteogenic-osteoclastic balance and the ensuing periodontal bone destruction. Accordingly, interventions targeting miR-143-3p in macrophages or employment of apoptosis inhibitor Z-VAD hold promise as effective therapeutic strategies for the management of PD. [ABSTRACT FROM AUTHOR]

Background: Osteoporosis has been recognized as a significant health issue in Thailand. Pharmacological interventions are important way to prevent fracture. However, one of the main challenges in selecting a medication is high cost, particularly for brand-name drugs. Data on generic bisphosphonate use in Thai are still lacking. Therefore, our study aimed to assess the efficacy and safety of generic risedronate in postmenopausal Thai women with osteoporosis. Methods: This prospective study was conducted at King Chulalongkorn Memorial Hospital, Bangkok, Thailand, from December 2022 to January 2024. Serum C-terminal cross-linking telopeptide of type I collagen (CTX) and procollagen type I N-propeptide (P1NP) were measured at baseline. All participants subsequently received 35 milligrams of oral risedronate once weekly for 52 weeks. Serum CTX and P1NP were remeasured at different time points. BMD was reevaluated at 52 weeks after risedronate treatment initiation. Results: A total of 80 participants were included. The mean age was 65.2 ± 6.6 years. The mean body mass index (BMI) was 23.45 ± 3.49 kg/m2. The median (IQR) serum CTX level at 12 weeks was significantly lower than that at baseline (0.28 (0.16–0.46) ng/mL versus 0.44 (0.26–0.64) ng/mL, respectively; p value < 0.01). The suppression of serum CTX was confirmed at 52 weeks after treatment initiation. Compared with those at baseline, the serum P1NP levels were significantly lower at 24 weeks after treatment initiation (30.33 (19.19–39.58) ng/mL versus 41.90 (30.33–68.67) ng/mL, respectively; p value < 0.01). In terms of the BMD assessment at 52 weeks, significant improvements were observed in both areal BMD (g/cm2) and T scores at all measured sites compared with baseline. The lumbar spine, femoral neck, and total hip BMD increased from baseline by 4.76%, 3.84% and 4.54%, respectively. Conclusion: Postmenopausal women with osteoporosis who were treated with generic risedronate demonstrated significant suppression of the bone remodelling process at 3, 6, and 12 months after treatment initiation. Additionally, significant improvements in the lumbar spine, femoral neck, and total hip BMD were observed at 12 months of therapy. These findings suggest that generic risedronate could be considered a reasonable and interesting option for treating postmenopausal women with osteoporosis in Thailand. [ABSTRACT FROM AUTHOR]

ABSTRACT Aims/Introduction Materials and Methods Results Conclusions Orthodontic treatment involves alveolar bone remodeling in response to mechanical loading, resulting in tooth movement through traction‐side bone formation and compression‐side bone resorption. However, there are conflicting reports regarding alveolar bone resorption during the orthodontic treatment of patients with diabetes.Diabetes was induced in 8‐week‐old C56BL/6J mice using streptozotocin (STZ). Four weeks after the injection of STZ, a mechanical load was applied between the first and second molars on the right side of the upper jaw using the Waldo method with orthodontic elastics in diabetic (DM) and normal (N) mice tooth movement, gene expression, osteoclast counts, alveolar bone residual volume, and bone beam structure were evaluated.The duration until spontaneous elastic loss was significantly longer in the DM group, suggesting that tooth movement may be inhibited in the diabetic state. The number of osteoclasts at 7 days after mechanical loading and the alveolar bone resorption were both significantly lower in the DM group. The gene expression levels of vascular endothelial growth factor (VEGF), a protein related to alveolar bone remodeling, and specificity protein 1 (SP1), a transcription factor of the VEGF gene, were significantly lower in the DM group than in the N group on the compression side of mechanical loading.Mechanical loading‐induced alveolar bone remodeling is suppressed in the diabetic state. Our results suggest that VEGF is a key molecule involved in impaired bone remodeling under mechanical loading in the diabetic state. [ABSTRACT FROM AUTHOR]

Malocclusions are common craniofacial malformations that cause quality of life and health problems if left untreated. Unfortunately, the current treatment for severe skeletal malocclusion is invasive surgery. Developing improved therapeutic options requires a deeper understanding of the cellular mechanisms responsible for determining jaw bone length. We have recently shown that neural crest mesenchyme (NCM) can alter jaw length by controlling the recruitment and function of mesoderm-derived osteoclasts. Transforming growth factor beta (TGF-β) signaling is critical to craniofacial development by directing bone resorption and formation, and heterozygous mutations in the TGF-β type I receptor (TGFBR1) are associated with micrognathia in humans. To identify the role of TGF-β signaling in NCM in controlling osteoclasts during mandibular development, the mandibles of mouse embryos deficient in the gene encoding Tgfbr1, specifically in NCM, were analyzed. Our laboratory and others have demonstrated that Tgfbr1fl/fl;Wnt1-Cre mice display significantly shorter mandibles with no condylar, coronoid, or angular processes. We hypothesize that TGF-β signaling in NCM can also direct late bone remodeling and further regulate late embryonic jaw bone length. Interestingly, analysis of mandibular bone based on micro-computed tomography and Masson’s trichrome revealed no significant difference in bone quality between the Tgfbr1fl/fl;Wnt1-Cre mice and controls, as measured by the bone perimeter/bone area, trabecular rod-like diameter, number and separation, and gene expression of collagen type 1 alpha 1 (Col1α1) and matrix metalloproteinase 13 (Mmp13). Although there was not a difference in localization of bone resorption within the mandible indicated by tartrate-resistant acid phosphatase (TRAP) staining, Tgfbr1fl/fl;Wnt1-Cre mice had approximately three-fold less osteoclast number and perimeter than controls. Gene expression of receptor activator of nuclear factor kappa-β (Rank) and Mmp9, markers of osteoclasts and their activity, also showed a three-fold decrease in Tgfbr1fl/fl;Wnt1-Cre mandibles. Evaluation of osteoblast-to-osteoclast signaling revealed no significant difference between Tgfbr1fl/fl;Wnt1-Cre mandibles and controls, leaving the specific mechanism unresolved. Finally, pharmacological inhibition of Tgfbr1 signaling during the initiation of bone mineralization and resorption significantly shortened jaw length in embryos. We conclude that TGF-β signaling in NCM decreases mesoderm-derived osteoclast number, that TGF-β signaling in NCM impacts jaw length late in development, and that this osteoblast-to-osteoclast communication may be occurring through an undescribed mechanism. [ABSTRACT FROM AUTHOR]

Background: The gut microbiota is a key regulator of bone metabolism. Investigating the relationship between the gut microbiota and bone remodeling has revealed new avenues for the treatment of bone-related disorders. Despite significant progress in understanding gut microbiota-bone interactions in mammals, research on avian species remains limited. Birds have unique bone anatomy and physiology to support egg-laying. However, whether and how the gut microbiota affects bone physiology in birds is still unknown. In this study, we utilized laying hens as a research model to analyze bone development patterns, elucidate the relationships between bone and the gut microbiota, and mine probiotics with osteomodulatory effects. Results: Aging led to a continuous increase in bone mineral density in the femur of laying hens. The continuous deposition of medullary bone in the bone marrow cavity of aged laying hens led to significant trabecular bone loss and weakened bone metabolism. The cecal microbial composition significantly shifted before and after sexual maturity, with some genera within the class Clostridia potentially linked to postnatal bone development in laying hens. Four bacterial strains associated with bone development, namely Blautia coccoides CML164, Fournierella sp002159185 CML151, Anaerostipes caccae CML199 (ANA), and Romboutsia lituseburensis CML137, were identified and assessed in chicks with low bacterial loads and chicken primary osteoblasts. Among these, ANA demonstrated the most significant promotion of bone formation both in vivo and in vitro, primarily attributed to butyrate in its fermentation products. A long-term feeding experiment of up to 72 weeks confirmed that ANA enhanced bone development during sexual maturity by improving the immune microenvironment of the bone marrow in laying hens. Dietary supplementation of ANA for 50 weeks prevented excessive medullary bone deposition and mitigated aging-induced trabecular bone loss. Conclusions: These findings highlight the beneficial effects of ANA on bone physiology, offering new perspectives for microbial-based interventions for bone-related disorders in both poultry and possibly extending to human health. 3YvVhM8B6L-RxYm8AZskZy Video Abstract [ABSTRACT FROM AUTHOR]

Highlights: Introduce the role of bioelectricity and the endogenous electric field in bone tissue and summarize different techniques to electrically stimulate cells and tissue. Highlight the latest progress in exploring electroactive hybrid biomaterials as well as self-powered systems such as triboelectric and piezoelectric-based nanogenerators and photovoltaic cell-based devices in bone tissue engineering. Emphasize the significance of simulating the target tissue's electrophysiological microenvironment and propose the opportunities and challenges faced by electroactive hybrid biomaterials and self-powered bioelectronics. The incidence of large bone defects caused by traumatic injury is increasing worldwide, and the tissue regeneration process requires a long recovery time due to limited self-healing capability. Endogenous bioelectrical phenomena have been well recognized as critical biophysical factors in bone remodeling and regeneration. Inspired by bioelectricity, electrical stimulation has been widely considered an external intervention to induce the osteogenic lineage of cells and enhance the synthesis of the extracellular matrix, thereby accelerating bone regeneration. With ongoing advances in biomaterials and energy-harvesting techniques, electroactive biomaterials and self-powered systems have been considered biomimetic approaches to ensure functional recovery by recapitulating the natural electrophysiological microenvironment of healthy bone tissue. In this review, we first introduce the role of bioelectricity and the endogenous electric field in bone tissue and summarize different techniques to electrically stimulate cells and tissue. Next, we highlight the latest progress in exploring electroactive hybrid biomaterials as well as self-powered systems such as triboelectric and piezoelectric-based nanogenerators and photovoltaic cell-based devices and their implementation in bone tissue engineering. Finally, we emphasize the significance of simulating the target tissue's electrophysiological microenvironment and propose the opportunities and challenges faced by electroactive hybrid biomaterials and self-powered bioelectronics for bone repair strategies. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusion To evaluate Hyuganatsu oranges (Citrus tamurana Hort. Ex Tanaka) derived arabinogalactan for bone turnover, we performed a randomized placebo‐controlled trial.Sixty‐three postmenopausal women were age‐stratified and randomly assigned to receive arabinogalactan‐rich hyuganatsu juice (study group) or a placebo drink (control group) for 90 days. We measured blood tartrate‐resistant acid phosphatase 5b (TRACP5b), type I procollagen N‐terminal propeptide (P1NP), and other bone turnover biomarker levels at baseline, days 45 and 90 (T90) of the intervention, and day 30 of recovery. Cumulative effects were compared between groups using repeated‐measures linear mixed model analysis. The primary endpoint was the difference between the pre‐ and post‐intervention TRACP5b and P1NP levels.Using repeated measures linear mixed model analysis, the study group had significantly lower TRACP5b and P1NP levels at day 90 than the control group (mean [95% confidence interval]; TRACP5b: 310.0 [269.2–350.9] vs. 386.4 [341.2–431.6] mU/dL; P1NP: 53.7 [48.6–58.7] vs. 70.3 [64.1–76.4] ng/mL), whereas other biomarker levels showed no change.Arabinogalactan‐rich Hyuganatsu juice suppressed bone mineral turnover and potentially improved ovarian hormone deficiency‐induced osteoporosis in postmenopausal women. [ABSTRACT FROM AUTHOR]

Osteoporosis becomes a global public health concern due to its rising prevalence and substantial impact on life quality. Salvia miltiorrhiza Bunge (Salviae Miltiorrhizae Radix et Rhizoma, SM) has been firstly recorded in Shen Nong's Herbal Classic, and is frequently prescribed in conjunction with other herbs for the management of osteoporosis. This systematic review aims to comprehensively analyze the recent advances of SM on osteoporosis in traditional Chinese clinical uses and preclinical investigations. Literature encompassing pertinent studies were systematically retrieved across multiple databases, including the PubMed, Web of Science, Chinese National Knowledge Infrastructure, Chinese VIP Database, and Chinese Biomedical Literature Database. Original investigations spanning from February 2014 to March 2024, including traditional Chinese medicine (TCM) clinical trials and preclinical studies, were employed to analyze the effects and actions of SM on osteoporosis. Thirtyeight TCM clinical trials were identified to employ SM in combination with other herbs for the management of primary and secondary osteoporosis. The overall efficacy was between 77% and 96.67%. Forty preclinical studies were identified to investigate the effects and actions of SM and/or its ingredients on osteoporosis. The anti-osteoporosis actions of this herb may be attributed to inhibit osteoclastogenesis/bone resorption and promote osteoblastogenesis/osteogenesis. The ethanol extracts and its ingredients (tanshinones) inhibit osteoclastogenesis/bone resorption by inhibiting the MAPK/NF-B/NFATc1 signaling pathway and cathepsin K-induced collagen degradation. Both ethanol extracts (tanshinones) and water extracts (Sal B and tanshinol) contribute to osteoblastogenesis by promoting osteogenesis and angiogenesis via activation of the Wnt/ß-catenin/VEGF and ERK/TAZ pathways, and eliminating ROS production targeting Nrf2/ARE/HO-1 pathway. In conclusions, SM may offer a novel strategy for osteoporosis management. Well-designed clinical trials are still needed to evaluate the actions of this herb and its ingredients on bone remodeling. [ABSTRACT FROM AUTHOR]

Cathepsin‐K (CTSK) is an osteoclast‐secreted cysteine protease that efficiently cleaves extracellular matrices and promotes bone homeostasis and remodeling, making it an excellent therapeutic target. Detection of CTSK activity in complex biological samples using tailored tools such as activity‐based probes (ABPs) will aid tremendously in drug development. Here, potent and selective CTSK probes are designed and created, comparing irreversible and reversible covalent ABPs with improved recognition components and electrophiles. The newly developed CTSK ABPs precisely detect active CTSK in mouse and human cells and tissues, from diseased and healthy states such as inflamed tooth implants, osteoclasts, and lung samples, indicating changes in CTSK's activity in the pathological samples. These probes are used to study how acidic pH stimulates mature CTSK activation, specifically, its transition from pro‐form to mature form. Furthermore, this study reveals for the first time, why intact cells and cell lysate exhibit diverse CTSK activity while having equal levels of mature CTSK enzyme. Interestingly, these tools enabled the discovery of active CTSK in human osteoclast nuclei and in the nucleoli. Altogether, these novel probes are excellent research tools and can be applied in vivo to examine CTSK activity and inhibition in diverse diseases without immunogenicity hazards. [ABSTRACT FROM AUTHOR]

The main aim of bone tissue engineering is to develop novel scaffold structures that integrate biological functionality with sufficient mechanical strength and properties. In this study, bone scaffolds were fabricated using polyether ether ketone (PEEK) via 3D printing, resulting in three different porous designs. To enhance their biological attributes, these scaffolds were coated with an alginate and carbon nanotube (CNT) composite using a freeze-drying technique. The biological characteristics of fabricated samples, such as biocompatibility and bioactivity, were evaluated in simulated body fluid (SBF). Field emission scanning electron microscopy (FE-SEM) analysis showed that the 3D-printed PEEK scaffolds had a porous, uniform, and interconnected architecture with pore sizes between 321–378 µm. Energy-dispersive X-ray spectroscopy (EDS) and X-ray diffraction (XRD) confirmed the formation of hydroxyapatite (HA) and bioactive calcium phosphate (Ca-P) on the scaffold surfaces, indicating their bioactivity. Cell biocompatibility was assessed using the MTT assay, which revealed a high cell viability rate of approximately 97% and no significant toxicity. Consequently, the 3D-printed PEEK scaffold coated with Alginate/0.3%wt CNT demonstrated promising microstructure, bioactivity, and biocompatibility, making it suitable for bone tissue regeneration. [ABSTRACT FROM AUTHOR]

Idiopathic osteoporosis (IOP) is a rare form of early-onset osteoporosis diagnosed in patients with no known metabolic or hormonal cause of bone loss and unknown pathogenesis. Patients with IOP commonly report both childhood fractures and family history of osteoporosis, raising the possibility of genetic etiologies of IOP. Whole-exome sequencing analyses of different IOP cohorts identified multiple variants in melatonin receptor 1A (MTNR1A) with a potential pathogenic outcome. A rare MTNR1A variant (rs374152717) was found in members of an Ashkenazi Jewish family with IOP, and an MTNR1A variant (rs28383653) was found in a nonrelated female IOP cohort (4%). Both variants occur at a substantially higher frequency in Ashkenazi Jewish individuals than in the general population. We investigated consequences of the heterozygous (rs374152717) variant [MTNR1Ac.184+1G>T (MTNR1Ac.184+1G>T)] on bone physiology. A mouse model of the human rs374152717 variant reproduced the low bone mass (BM) phenotype of young-adult patients with IOP. Low BM occurred because of induction of senescence in mutant osteoblasts followed by compromised differentiation and function. In human cells, introduction of rs374152717 led to translation of a nonfunctional protein and subsequent dysregulation of melatonin signaling. These studies provide evidence that MTNR1A mutations entail a genetic etiology of IOP and establish the rs374152717 variant as a loss-of-function allele that impairs bone turnover by inducing senescence in osteoblasts. The higher prevalence of the MTNR1A variants identified in IOP cohorts versus the general population indicates a greater risk of IOP in those carrying these variants, especially Ashkenazi Jewish individuals bearing the rs374152717 variant. Editor's summary: Osteoporosis with no known cause (idiopathic osteoporosis, or IOP) results in weak bones and fractures in otherwise healthy individuals younger than 50 years of age. Bisikirska et al. identified rare genetic variants in the melatonin receptor 1A (MTNR1A) gene enriched in cohorts of individuals with IOP. Heterozygosity of one particular loss-of-function variant in mice reproduced many of the patients' symptoms. This study provides evidence of a genetic component in IOP and may have downstream consequences for genetic screening as well as for the longstanding advocation for the use of melatonin in this setting. —Catherine Charneski [ABSTRACT FROM AUTHOR]

Bone and joint-related diseases, including osteoarthritis (OA), rheumatoid arthritis (RA), and bone tumors, pose significant health challenges due to their debilitating effects on the musculoskeletal system. 14-3-3 proteins, a family of conserved regulatory molecules, play a critical role in the pathology of these diseases. This review discusses the intricate structure and multifunctionality of 14-3-3 proteins, their regulation of signaling pathways, and their interactions with other proteins. We underscore the significance of 14-3-3 proteins in the regulation of osteoblasts, osteoclasts, chondrocytes, and bone remodeling, all key factors in the maintenance and dysfunction of bone and joint systems. Specific focus is directed toward elucidating the contribution of 14-3-3 proteins in the pathology of OA, RA, and bone malignancies, where dysregulated 14-3-3-mediated signaling cascades have been implicated in the disease processes. This review illuminates how the perturbation of 14-3-3 protein interactions can lead to the pathological manifestations observed in these disorders, including joint destruction and osteolytic activity. We highlight cutting-edge research that positions 14-3-3 proteins as potential biomarkers for disease progression and as innovative therapeutic targets, offering new avenues for disease intervention and management. [ABSTRACT FROM AUTHOR]

Abnormal subchondral bone remodeling plays a pivotal role in the progression of osteoarthritis (OA). Here, we analyzed subchondral bone samples from OA patients and observed a significant upregulation of ubiquitin carboxy-terminal hydrolase L1 (UCHL1) specifically in subchondral bone osteoclasts. Notably, we found a strong correlation between UCHL1 expression and osteoclast activity in the subchondral bone during OA progression in both human and murine models. Conditional UCHL1 deletion in osteoclast precursors exacerbated OA progression, while its overexpression, mediated by adeno-associated virus 9, alleviated this process in male mice. Mechanistically, RANKL stimulates UCHL1 expression in osteoclast precursors, subsequently stabilizing CD13, augmenting soluble CD13 (sCD13) release, and triggering an autocrine inhibitory effect on the MAPK pathway, thereby suppressing osteoclast formation. These findings unveil a previously unidentified negative feedback loop, RANKL-UCHL1-sCD13, that modulates osteoclast formation and presents a potential therapeutic target for OA. Abnormal subchondral bone remodeling plays a pivotal role in the progression of osteoarthritis. Here, the authors reveal a negative feedback loop, RANKL-UCHL1-sCD13, which limits osteoclastogenesis in the subchondral bone to prevent osteoarthritis progression. [ABSTRACT FROM AUTHOR]