A Novel Heterozygous Mutation c.1627G>T (p.Gly543Cys) in the SLC34A1 Gene in a Male Patient with Recurrent Nephrolithiasis and Early Onset Osteopenia: A Case Report.

Serum phosphate concentration is regulated by renal phosphate reabsorption and mediated by sodium-phosphate cotransporters. Germline mutations in genes encoding these cotransporters have been associated with clinical phenotypes, variably characterized by hyperphosphaturia, hypophosphatemia, recurrent kidney stones, skeletal demineralization, and early onset osteoporosis. We reported a 33-year-old male patient presenting a history of recurrent nephrolithiasis and early onset osteopenia in the lumbar spine and femur. He was tested, through next generation sequencing (NGS), by using a customized multigenic panel containing 33 genes, whose mutations are known to be responsible for the development of congenital parathyroid diseases. Two further genes, SLC34A1 and SLC34A3, encoding two sodium-phosphate cotransporters, were additionally tested. A novel germline heterozygous mutation was identified in the SLC34A1 gene, c.1627G>T (p.Gly543Cys), currently not reported in databases of human gene mutations and scientific literature. SLC34A1 germline heterozygous mutations have been associated with the autosomal dominant hypophosphatemic nephrolithiasis/osteoporosis type 1 (NPHLOP1). Consistently, alongside the clinical features of NPHLOP1, our patient experienced recurrent nephrolithiasis and lumbar and femoral osteopenia at a young age. Genetic screening for the p.Gly453Cys variant and the clinical characterization of his first-degree relatives associated the presence of the variant in one younger brother, presenting renal colic and microlithiasis, suggesting p.Gly453Cys is possibly associated with renal altered function in the NPHLOP1 phenotype.

Declining histone acetyltransferase GCN5 represses BMSC-mediated angiogenesis during osteoporosis.

Angiogenesis is disrupted in age-related and postmenopausal osteoporosis. However, the mechanisms of the disorder remain elusive. We confirmed in this study that, in accordance with the decrease of H-type vessels, the proangiogenic potential of bone marrow-derived mesenchymal stem cells (BMSCs) declined during osteoporosis. Screening of the histone acetyltransferase family revealed that GCN5 decreased in BMSCs derived from osteoporotic femur. Further analysis identified that GCN5 plays important roles in regulating the proangiogenic potential of BMSCs. GCN5 promoted BMSC-mediated angiogenesis by enhancing H3K9ac levels on the promoter of Vegf The decrease of GCN5 in osteoporotic BMSCs led to the decline of proangiogenic capacity. Accordingly, overexpression of GCN5 enhanced the proangiogenic potency of osteoporotic BMSCs. Furthermore, recovering GCN5 expression in vivo by lentiviral expression vector significantly attenuated the loss of angiogenesis in ovariectomized mouse femurs. Our study results revealed an epigenetic mechanism controlling BMSC-mediated angiogenesis and provided a novel therapeutic target for osteoporosis treatment.-Jing, H., Liao, L., Su, X., Shuai, Y. Zhang, X., Deng, Z., Jin, Y. Declining histone acetyltransferase GCN5 represses BMSC-mediated angiogenesis during osteoporosis.

Dihydrotanshinone I attenuates estrogen-deficiency bone loss through RANKL-stimulated NF-κB, ERK and NFATc1 signaling pathways.

Postmenopausal osteoporosis, a chronic condition that predominantly affects postmenopausal women, presents a significant impediment to their overall well-being. The condition arises from estrogen deficiency, leading to enhanced osteoclast activity. Salvia miltiorrhiza, a well-established Chinese herbal medicine with a history of clinical use for osteoporosis treatment, contains diverse active constituents that have shown inhibitory effects on osteoclast formation and bone loss. Dihydrotanshinone I (DTI), a phenanthrenonequinone compound derived from the root of Salvia miltiorrhiza, has been identified as a potential therapeutic agent, although its mechanism of action on osteoclasts remains elusive. In this study, we aimed to elucidate the inhibitory potential of DTI on RANKL-induced osteoclastogenesis. We observed the ability of DTI to effectively impede the expression of key osteoclast-specific genes and proteins, as assessed by Real-time PCR and Western Blotting analyses. Mechanistically, DTI exerted its inhibitory effects on osteoclast formation by modulating critical signaling pathways including NF-κB, ERK, and calcium ion signaling. Notably, DTI intervention disrupted the nuclear translocation and subsequent transcriptional activity of the NFATc1, thus providing mechanistic insights into its inhibitory role in osteoclastogenesis. To further assess the therapeutic potential of DTI, we employed an ovariectomized osteoporosis animal model to examine its impact on bone loss. Encouragingly, DTI demonstrated efficacy in mitigating bone loss induced by estrogen deficiency. In conclusion, our investigation elucidates the ability of DTI to regulate multiple signaling pathways activated by RANKL, leading to the inhibition of osteoclast formation and prevention of estrogen-deficiency osteoporosis. Consequently, DTI emerges as a promising candidate for the treatment of osteoporosis.

Can Denosumab be used in combination with Doxorubicin in Osteosarcoma?

Osteosarcoma is an aggressive bone tumor of the pediatric age. It is therefore important to improve conventional therapies (chemotherapy and surgery). Anticancer drugs often cause osteoporosis due to a misbalance of RANK/RANK-L/OPG pathway. Denosumab is a monoclonal antibody with high affinity and specificity to RANK-L, the ligand released by osteoblasts that enhances osteoclasts differentiation and bone resorption. It is used in osteoporosis and in other conditions characterized by bone mass loss. Doxorubicin is a chemotherapic drug used in several kinds of tumors, and also patients treated with it often develop osteoporosis. We investigated the effects of Denosumab alone and in combination with Doxorubicin, in two human osteosarcoma cell lines (MG63 and U-2 OS). We evaluated the effect of these treatments on apoptosis, cell cycle progression, invasion capacity and bone metabolism. We observed for the first time an anti-invasive effect of Denosumab in OS cells and confirmed its anti-osteoporotic activity also in Osteosarcoma. On the other hand, we demonstrate that Denosumab not only does not affect apoptosis and cell cycle progression, but when used in combination with Doxorubicin, it causes an unexpected reduction of its activity. These results indicate that the presence of Denosumab might inhibit the efficacy of the chemotherapic drug. In conclusion, while our results certainly support and confirm the efficacy of Denosumab in Osteoporosis, we discourage the use of Denosumab in addition to conventional chemotherapy in Osteosarcoma, even though, certainly further investigations are necessary to better clarify the clinical role of this monoclonal antibody in cancer.

Impaired autophagy triggered by HDAC9 in mesenchymal stem cells accelerates bone mass loss.

BACKGROUND: Bone mass loss in aging is linked with imbalanced lineage differentiation of bone marrow mesenchymal stem cells (BMMSCs). Recent studies have proved that histone deacetylases (HDACs) are regarded as key regulators of bone remodeling. However, HDACs involve in regulating BMMSC bio-behaviors remain elusive. Here, we investigated the ability of HDAC9 on modulation of autophagy and its significance in lineage differentiation of BMMSCs. METHODS: The effects of HDAC9 on lineage differentiation of BMMSCs and autophagic signaling were assessed by various biochemical (western blot and ChIP assay), morphological (TEM and confocal microscopy), and micro-CT assays. RESULTS: Sixteen-month mice manifested obvious bone mass loss and marrow fat increase, accompanied with decreased osteogenic differentiation and increased adipogenic differentiation of BMMSCs. Further, the expression of HDAC9 elevated in bone and BMMSCs. Importantly, HDAC9 inhibitors recovered the lineage differentiation abnormality of 16-month BMMSCs and reduced p53 expression. Mechanistically, we revealed that HDAC9 regulated the autophagy of BMMSCs by controlling H3K9 acetylation in the promoters of the autophagic genes, ATG7, BECN1, and LC3a/b, which subsequently affected their lineage differentiation. Finally, HDAC9 inhibition improved endogenous BMMSC properties and promoted the bone mass recovery of 16-month mice. CONCLUSIONS: Our data demonstrate that HDAC9 is a key regulator in a variety of bone mass by regulating autophagic activity in BMMSCs and thus a potential target of age-related bone loss treatment.

Cav 1.2 regulates osteogenesis of bone marrow-derived mesenchymal stem cells via canonical Wnt pathway in age-related osteoporosis.

AIMS: Age-related bone mass loss is one of the most prevalent diseases that afflict the elderly population. The decline in the osteogenic differentiation capacity of bone marrow-derived mesenchymal stem cells (BMMSCs) is regarded as one of the central mediators. Voltage-gated Ca2+ channels (VGCCs) play an important role in the regulation of various cell biological functions, and disruption of VGCCs is associated with several age-related cellular characteristics and systemic symptoms. However, whether and how VGCCs cause the decreased osteogenic differentiation abilities of BMMSCs have not been fully elucidated. METHODS: Voltage-gated Ca2+ channels related genes were screened, and the candidate gene was determined in several aging models. Functional role of determined channel on osteogenic differentiation of BMMSCs was investigated through gain and loss of function experiments. Molecular mechanism was explored, and intervention experiments in vivo and in vitro were performed. RESULTS: We found that Cav 1.2 was downregulated in these aging models, and downregulation of Cav 1.2 in Zmpste24-/- BMMSCs contributed to compromised osteogenic capacity. Mechanistically, Cav 1.2 regulated the osteogenesis of BMMSCs through canonical Wnt/ß-catenin pathway. Moreover, upregulating the activity of Cav 1.2 mitigated osteoporosis symptom in Zmpste24-/- mice. CONCLUSION: Impaired osteogenic differentiation of Zmpste24-/- BMMSCs can be partly attributed to the decreased Cav 1.2 expression, which leads to the inhibition of canonical Wnt pathway. Bay K8644 treatment could be an applicable approach for treating age-related bone loss by ameliorating compromised osteogenic differentiation capacity through targeting Cav 1.2 channel.

[Analysis of BPPV in patients with bone mineral density results].

Objective:Analyze BPPV in patients with ultrasonic bone mineral density to investigate the relationship between the BPPV and bone density. Method:A total of 88 included subjects were selected from patients admitted to the Otolaryngological Department of Renhe Hospital, Beijing. Meanwhile, 76 healthy persons were included as control. The control group had similar age and gender distributions to the test group, and all healthy subjects had no history of vertigo in recent one year. Both groups underwent regular otolaryngological examinations, videonystagmography（VNG）,ultrasound bone densitometer test. According to gender, age, listening to group. Result:①Bone density of the test group was significantly lower than the control group（-2.010±1.658 vs 0.3605±0.875）,the difference was statistically significant（P<0.01）；②Incidence rates of bone mass loss（35 in 88,39.77%）and osteoporosis（26 in 88, 29.55%）bone mineral density decreased incidence of 69.32%, in the test group was significantly higher than that in the control group（bone mass loss, 13 in 76, 17.10%; osteoporosis 6 in 76,7.89%）, bone mineral density decreased incidence of 25.00%,the difference was statistically significant（P<0.01）；③The test group and control group according to different age groups, the test group all ages bone density T values significantly lower than the control group（P<0.01）,the difference was statistically significant. In the age groups, the incidence of bone loss was higher in the test group than that in the control group, the difference was statistically significant(P<0.01).④In the gender group, bone density of the test group women were significantly lower than the control group, the difference was statistically significant（P<0.05）； especially after the age of 60.⑤In the test group, 27 cases of bone mineral density is normal, with normal hearing 19 cases (70.37%), hearing loss 8 cases(29.63%);61 cases of bone loss, including normal hearing 48 cases (78.69%),hearing loss 13 cases (21.31%). The difference between hearing loss and bone loss had no statistical significance(P>0.05).⑥The logistic regression results showed that the prompt Higher bone mineral density T value was BPPV protection factors, OR=0.686,(P<0.01,95%CI: 1.32-5.85). Conclusion:BPPV in patients with bone mineral density value is lower than the normal control group, there is a higher incidence of bone loss, at the same time, along with the age increasing on the rise, especially women.

Radiomorphometric indices of mandibular bones in an 18th century population.

OBJECTIVE: To estimate four radiomorphometric indices of mandibular bones in an 18th century population sample, and possibly associate the findings with bone mass loss related to sex, age, nutritional habits and pathologies reflecting on the bone. DESIGN: Thirty-six sculls (31 males, 5 females), recovered from the crypt of Pozega Cathedral in Croatia were analyzed. Age estimation was based on tooth wear, and Eichner class was determined according to the number of occlusal supporting zones. The parameters in recording analogue orthopantomographs were set to constant current of 16 mA, exposure time of 14.1s, and voltage between 62-78 kV. Films were processed in an automatic dark chamber processor for 12 min, and digitized at 8-bit, 300 dpi. The thickness of the mandibular cortex was assessed below the mental foramen (MI), at antegonion (AI), at gonion (GI). Qualitative mandibular cortical index (MCI) was assessed. RESULTS: Average values of MI, AI and GI were 3.97 ± 0.94 mm, 2.98 ± 0.56 mm, and 1.99 ± 0.55 mm, respectively. Statistically significant differences between males and females were found for AI right (p=0.014), GI left (p=0.010) and GI average (p=0.006), and were in all cases higher in males. There were no statistically significant differences between age groups for either index (p>0.05). Considering Eichner classification the differences were not significant for MI (p=0.422), AI (p=0.516), and GI (p=0.443), but in Eichner classes II, MCI was significantly higher (p=0.02). CONCLUSION: The obtained data does not suggest generalized malnutrition or calcium, phosphorus and vitamin D deprivation in the historic population studied.

Association between serum uric acid and bone health in general population: a large and multicentre study.

Previous studies proposed that serum uric acid (UA), an endogenous antioxidant, could be a protective factor against bone loss. However, recently, a study with a population of US adults did not note the protective effects of serum UA. Therefore, the exact association between serum UA and bone health remains unclear. We performed a retrospective consecutive cohort study in a Chinese population to examine the association between serum UA and bone health. This cross-sectional study included 17,735 individuals who underwent lumbar spine bone mineral density (BMD) measurements as part of a health examination. In covariance analyses (multivariable-adjusted), a high serum UA level was associated with a high BMD, T-score, and Z-score. In binary logistic regression analyses (multivariable-adjusted), a high serum UA level was associated with low odds ratios (ORs) for at least osteopenia and osteoporosis in male (age ≥50 years) (OR = 0.72-0.60 and OR = 0.49-0.39, respectively) and postmenopausal female participants (OR = 0.61-0.51 and OR = 0.66-0.49, respectively). In conclusion, serum UA is associated with BMD, the T-score, and the Z-score, and has a strong protective effect against at least osteopenia and osteoporosis.

Cost-effectiveness Analysis of Denosumab in the Prevention of Skeletal-related Events in Patients with Prostate Cancer in Kazakhstan.

INTRODUCTION: Bone mass loss (BML) is one of the adverse effects of oncological chemotherapy, especially in cases of hormonal types of cancer, such as a prostate cancer (PC). BML is strongly associated with skeletal-related events (SREs), therefore decreasing the quality of patient's life. Denosumab shows an advantage over zoledronic acid (ZA) in delaying the first onset of SREs and subsequent SREs in adults with PC in several phase III clinical trials. Since generic ZA recently became available, the purpose of the present study was to assess the cost-effectiveness of denosumab vs. brand or generic ZA in the prevention of SREs in Kazakhstani patients with PC. METHODS: A Markov model was constructed in Tree-Age Pro 2013 software program with 4-week model cycles to analyze the cost-effectiveness of the treatments from the perspective of Ministry of Health (MoH) over a 10-year PC cohort. Direct costs (in Kazakhstani monetary units "tenge" in 2014) included costs of drug, SRE (pathologic fracture, surgery to bone, radiation to bone, spinal cord compression), and adverse events treatment. All costs were discounted for 3% per year. Effectiveness was appraised based on the number of SREs. Health states were defined according to SRE occurrence, SRE history, and death. The model assumed that a maximum of 1 SRE could occur in each cycle. Transition probabilities were derived from the relevant phase III trials. Results were present in the incremental total cost per SRE avoided. One-way sensitivity analyses were performed to examine the robustness of the model. RESULTS: Over the 10-year period, denosumab incurred 103,091 tenge higher costs than brand ZA, 677,133 tenge higher costs than generic ZA, and 0.58 fewer SREs per patient with PC. The estimated incremental total direct costs per SRE avoided with the use of denosumab were 177,743 tenge (instead of brand ZA) and 1,167,470 tenge (instead of generic ZA). Results were robust to one-way sensitivity analyses. CONCLUSIONS: With the assumption that brand and generic ZAs are equally effective in the prevention of SREs in PC patients, denosumab seems to be a cost-effective alternative for brand ZA (insignificant difference in costs - less than 5%) and a costly alternative for generic ZA from the perspective of MoH of Kazakhstan.