Vitamin K is the cofactor for the hepatic carboxylation of glutamic acid residues in a number of proteins including the procoagulants factors ll, Vll, lX, and X. The role of vitamin K in normal bone function is not fully understood. Inherited deficiency of vitamin K dependent coagulation factors is a rare bleeding disorder reported only in a few patients. Here we present an 18-month old child who presented with osteopeni due to inherited vitamin K deficiency. While the patient had high bone specific alkaline phosphatase and parathyroid hormone levels and low osteocalcin and bone mineral density values, with the regular supplementation of vitamin K all the mentioned parameters returned to normal values.
Bone Density ; Bone Diseases, Metabolic/etiology ; Human ; Infant ; Male ; Osteocalcin/blood ; Prothrombin Time ; Vitamin K Deficiency/blood/complications/*genetics

BACKGROUND: Osteopenia has been well documented in adolescent idiopathic scoliosis (AIS). Bone marrow stem cells (BMSCs) are a crucial regulator of bone homeostasis. Our previous study revealed a decreased osteogenic ability of BMSCs in AIS-related osteopenia, but the underlying mechanism of this phenomenon remains unclear. METHODS: A total of 22 AIS patients and 18 age-matched controls were recruited for this study. Anthropometry and bone mass were measured in all participants. Bone marrow blood was collected for BMSC isolation and culture. Osteogenic and adipogenic induction were performed to observe the differences in the differentiation of BMSCs between the AIS-related osteopenia group and the control group. Furthermore, a total RNA was extracted from isolated BMSCs to perform RNA sequencing and subsequent analysis. RESULTS: A lower osteogenic capacity and increased adipogenic capacity of BMSCs in AIS-related osteopenia were revealed. Differences in mRNA expression levels between the AIS-related osteopenia group and the control group were identified, including differences in the expression of LRRC17 , DCLK1 , PCDH7 , TSPAN5 , NHSL2 , and CPT1B . Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed several biological processes involved in the regulation of autophagy and mitophagy. The Western blotting results of autophagy markers in BMSCs suggested impaired autophagic activity in BMSCs in the AIS-related osteopenia group. CONCLUSION Our study revealed that BMSCs from AIS-related osteopenia patients have lower autophagic activity, which may be related to the lower osteogenic capacity and higher adipogenic capacity of BMSCs and consequently lead to the lower bone mass in AIS patients.
Humans ; Adolescent ; Scoliosis/genetics* ; Cell Differentiation/physiology* ; Osteogenesis/genetics* ; Bone Diseases, Metabolic/genetics* ; Kyphosis ; Autophagy/genetics* ; Bone Marrow Cells ; Cells, Cultured ; Doublecortin-Like Kinases

Sympathetic cues via the adrenergic signaling critically regulate bone homeostasis and contribute to neurostress-induced bone loss, but the mechanisms and therapeutics remain incompletely elucidated. Here, we reveal an osteoclastogenesis-centered functionally important osteopenic pathogenesis under sympatho-adrenergic activation with characterized microRNA response and efficient therapeutics. We discovered that osteoclastic miR-21 was tightly regulated by sympatho-adrenergic cues downstream the β2-adrenergic receptor (β₂AR) signaling, critically modulated osteoclastogenesis in vivo by inhibiting programmed cell death 4 (Pdcd4), and mediated detrimental effects of both isoproterenol (ISO) and chronic variable stress (CVS) on bone. Intriguingly, without affecting osteoblastic bone formation, bone protection against ISO and CVS was sufficiently achieved by a (D-Asp₈)-lipid nanoparticle-mediated targeted inhibition of osteoclastic miR-21 or by clinically relevant drugs to suppress osteoclastogenesis. Collectively, these results unravel a previously underdetermined molecular and functional paradigm that osteoclastogenesis crucially contributes to sympatho-adrenergic regulation of bone and establish multiple targeted therapeutic strategies to counteract osteopenias under stresses.
Adrenergic Agents/pharmacology* ; Apoptosis Regulatory Proteins/pharmacology* ; Bone Diseases, Metabolic/metabolism* ; Humans ; Liposomes ; MicroRNAs/genetics* ; Nanoparticles ; Osteoclasts ; Osteogenesis/physiology* ; RNA-Binding Proteins/pharmacology*

BACKGROUND: Congenital scoliosis (CS) is a complex spinal malformation of unknown etiology with abnormal bone metabolism. Fibroblast growth factor 23 (FGF23), secreted by osteoblasts and osteocytes, can inhibit bone formation and mineralization. This research aims to investigate the relationship between CS and FGF23. METHODS: We collected peripheral blood from two pairs of identical twins for methylation sequencing of the target region. FGF23 mRNA levels in the peripheral blood of CS patients and age-matched controls were measured. Receiver operator characteristic (ROC) curve analyses were conducted to evaluate the specificity and sensitivity of FGF23. The expression levels of FGF23 and its downstream factors fibroblast growth factor receptor 3 (FGFr3)/tissue non-specific alkaline phosphatase (TNAP)/osteopontin (OPN) in primary osteoblasts from CS patients (CS-Ob) and controls (CT-Ob) were detected. In addition, the osteogenic abilities of FGF23-knockdown or FGF23-overexpressing Ob were examined. RESULTS: DNA methylation of the FGF23 gene in CS patients was decreased compared to that of their identical twins, accompanied by increased mRNA levels. CS patients had increased peripheral blood FGF23 mRNA levels and decreased computed tomography (CT) values compared with controls. The FGF23 mRNA levels were negatively correlated with the CT value of the spine, and ROCs of FGF23 mRNA levels showed high sensitivity and specificity for CS. Additionally, significantly increased levels of FGF23, FGFr3, OPN, impaired osteogenic mineralization and lower TNAP levels were observed in CS-Ob. Moreover, FGF23 overexpression in CT-Ob increased FGFr3 and OPN levels and decreased TNAP levels, while FGF23 knockdown induced downregulation of FGFr3 and OPN but upregulation of TNAP in CS-Ob. Mineralization of CS-Ob was rescued after FGF23 knockdown. CONCLUSIONS Our results suggested increased peripheral blood FGF23 levels, decreased bone mineral density in CS patients, and a good predictive ability of CS by peripheral blood FGF23 levels. FGF23 may contribute to osteopenia in CS patients through FGFr3/TNAP / OPN pathway.
Humans ; Osteopontin/genetics* ; Alkaline Phosphatase/metabolism* ; Receptor, Fibroblast Growth Factor, Type 3/metabolism* ; Scoliosis/genetics* ; Osteoblasts/metabolism* ; Calcinosis ; RNA, Messenger/metabolism* ; Bone Diseases, Metabolic/metabolism* ; Fibroblast Growth Factors/genetics*

The aims of this study were to investigate the relationships between the production of interleukin-1 (IL-1), and IL-6 system by whole blood cells, and bone mineral density (BMD), and polymorphisms in IL-1 system and IL-6 gene in postmenopausal Korean women. The production of IL-1alpha, IL-1beta, IL-1 receptor antagonist (IL-1ra), IL-6, and soluble IL-6 receptor (sIL-6r) by lipopolysaccharide-stimulated whole blood cells was measured by ELISA in 110 subjects. Serum osteocalcin, C-telopeptide of type I collagen, and BMD at lumbar spine and proximal femur were measured. IL-1alphaC(-889)T polymorphism, IL-1beta C(-511)T polymorphism, 86-base pair variable number tandem repeat polymorphism in the IL-1ra gene, and IL-6 C(-634)G polymorphism were analyzed. The production of IL-1beta correlated positively with BMD at femoral neck, whereas the production of other ILs did not correlate with BMD at the skeletal sites examined. No significant differences in the production of ILs were observed among normal, osteopenic and osteoporotic postmenopausal women, and among the different IL system polymorphisms groups studied. No correlation between bone turnover markers and the production of ILs was noted. In conclusion IL-1beta may regulate bone metabolism at femoral neck, and the IL system polymorphism do not affect the production of ILs by whole blood cells.
Aged ; Blood Cells/drug effects/immunology ; Bone Density/*genetics/*immunology ; Bone Diseases, Metabolic/blood/genetics/immunology ; Cytokines/*biosynthesis/blood ; Female ; Humans ; In Vitro ; Interleukin-1/biosynthesis/blood/genetics ; Interleukin-6/biosynthesis/blood/genetics ; Interleukins/*genetics ; Lipopolysaccharides/pharmacology ; Middle Aged ; Osteoporosis, Postmenopausal/blood/genetics/immunology ; *Polymorphism, Genetic ; Receptors, Interleukin-6/biosynthesis/blood/genetics ; Research Support, Non-U.S. Gov't ; Sialoglycoproteins/biosynthesis/blood/genetics

OBJECTIVETo investigate the association of bone metabolism related genes polymorphisms with the effect of raloxifene hydrochloride(RLX) on bone mineral density (BMD) and bone turnover markers in postmenopausal women with osteoporosis.

METHODSA total of 68 unrelated postmenopausal women with osteoporosis of Han ethnicity aged 47-74 years were randomly divided into 2 groups of 34 women: RLX group (60 mg were given daily for 12 months) and placebo group. BMD and bone turnover markers were measured at baseline, 6 and 12 months after treatment. The polymorphisms of Xba I and Pvu II sites in estrogen receptor 1 gene(ESR1), Ras I site in ESR2 gene, and start codon (Fok I) and CDX2 binding sites in vitamin D receptor gene (VDR) were analyzed.

RESULTSA total of 58 patients completed 12 months of study period. By the end of study, the increased percentage of BMD in lumbar spine 2-4 (L2-4), total hip, and trochanter were found significantly different between RLX group and placebo group(P<0.05), and the decreased percentage of C-telopeptide and osteocalcin were significantly different between the two groups (P<0.01). The BMD of total hip and trochanter of women with FF genotypes of VDR Fok I site were decreased by 1.98%+/-4.86% and 2.26%+/-4.73% respectively in the RLX group, but those of women with Ff/ff genotypes were increased by 2.52%+/-2.75% and 2.74 %+/-2.97%, respectively(P<0.05). Moreover, the total hip BMD of women with PP/Pp genotypes of ESR1 Pvu II site was increased by 2.12%+/-2.78%, and of women with pp genotype it was decreased by 1.34%+/-3.73%(P<0.05). However, no significant association was observed of the polymorphisms of five sites with the changes of BMD and bone turnover markers in the placebo group.

CONCLUSIONThe effect of RLX on BMD in postmenopausal women with osteoporosis is regulated by the polymorphisms of Fok I of VDR gene and Pvu II of ESR1 gene. The study is valuable to select this drug according to genotype of patients in clinical.

Aged ; Biomarkers ; metabolism ; Bone Density ; drug effects ; genetics ; Bone Diseases, Metabolic ; genetics ; metabolism ; Bone Remodeling ; drug effects ; genetics ; Bone and Bones ; drug effects ; Double-Blind Method ; Female ; Humans ; Middle Aged ; Osteoporosis ; drug therapy ; Osteoporosis, Postmenopausal ; drug therapy ; Polymorphism, Genetic ; Postmenopause ; drug effects ; Raloxifene Hydrochloride ; pharmacology ; therapeutic use ; Selective Estrogen Receptor Modulators ; pharmacology ; Women

Androgen receptor (AR) gene has been extensively studied in diverse clinical conditions. In addition to the point mutations, trinucleotide repeat (CAG and GGN) length polymorphisms have been an additional subject of interest and controversy among geneticists. The polymorphic variations in triplet repeats have been associated with a number of disorders, but at the same time contradictory findings have also been reported. Further, studies on the same disorder in different populations have generated different results. Therefore, combined analysis or review of the published studies has been of much value to extract information on the significance of variations in the gene in various clinical conditions. AR genetics has been reviewed extensively but until now review articles have focused on individual clinical categories such as androgen insensitivity, male infertility, prostate cancer, and so on. We have made the first effort to review most the aspects of AR genetics. The impact of androgens in various disorders and polymorphic variations in the AR gene is the main focus of this review. Additionally, the correlations observed in various studies have been discussed in the light of in vitro evidences available for the effect of AR gene variations on the action of androgens.
Androgen-Insensitivity Syndrome ; genetics ; physiopathology ; Bone Diseases, Metabolic ; genetics ; physiopathology ; Breast Neoplasms ; genetics ; physiopathology ; Cognition Disorders ; genetics ; physiopathology ; Digestive System Diseases ; genetics ; physiopathology ; Female ; Genital Neoplasms, Female ; genetics ; physiopathology ; Genital Neoplasms, Male ; genetics ; physiopathology ; Humans ; Infertility, Male ; genetics ; Male ; Muscular Atrophy, Spinal ; genetics ; physiopathology ; Phenotype ; Point Mutation ; Polycystic Ovary Syndrome ; genetics ; physiopathology ; Polymorphism, Genetic ; Pre-Eclampsia ; genetics ; physiopathology ; Pregnancy ; Receptors, Androgen ; genetics ; physiology ; Schizophrenia ; genetics ; physiopathology ; Testosterone ; deficiency ; Trinucleotide Repeats

OBJECTIVETo explore whether the intake of dietary carotenoids could protect against skeletal fluorosis in Guizhou province in which coal-burning fluorosis is endemic.

METHODSA case-control study of 196 patients with skeletal fluorosis and 196 age and gender-matched controls was conducted in Zhijin, Guizhou Province. Face-to-face interviews were conducted to assess habitual dietary intake using a 75-item food frequency questionnaire and various covariates with structured questionnaires. Urinary fluoride was measured using an ion-selective electrode method. The genotype of superoxide dismutase 2 (SOD2) rs11968525 was detected by TaqMan method.

RESULTSWe observed significant dose-dependent inverse associations of skeletal fluorosis with intake of β-carotene, lutein/zeaxanthin, lycopene, and total carotenoids (P-trend = 0.002 to 0.018), whereas α-carotene and β-cryptoxanthin intakes were not found to be related to skeletal fluorosis, after adjustment for potential confounders. The adjusted ORs and 95% CI of skeletal fluorosis for the highest versus lowest quartile were 0.30 (0.10, 0.86) for β-carotene, 0.23 (0.08, 0.66) for lycopene, 0.26 (0.10, 0.75) for lutein/zeaxanthin and 0.34 (0.14, 0.74) for total carotenoids (all P-trend < 0.05). Stratified analyses showed that the protective effects of lutein/zeaxanthin and total carotenoids on skeletal fluorosis were more evident for individuals with the AG+AA genotypes of SOD2 (rs11968525).

CONCLUSIONIncreased intakes of β-carotene, lutein/zeaxanthin, lycopene, and total carotenoids are independently associated with a lower risk of coal-burning skeletal fluorosis. SOD2 (rs11968525) polymorphisms might modify the inverse associations between dietary carotenoids and skeletal fluorosis.

Bone Diseases, Metabolic ; genetics ; prevention & control ; urine ; Carotenoids ; administration & dosage ; Case-Control Studies ; China ; Coal ; Energy Intake ; Environmental Exposure ; analysis ; Feeding Behavior ; Female ; Fluoride Poisoning ; genetics ; prevention & control ; urine ; Fluorides ; urine ; Humans ; Middle Aged ; Polymorphism, Genetic ; Superoxide Dismutase ; genetics ; Surveys and Questionnaires