BACKGROUND: Osteogenesis imperfecta (OI) is a group of connective tissue disease characterized by propensity to fractures following minimal trauma. OI is a lifelong inheritable disease and currently has no definitive cure. Management goals are directed towards prevention of fractures, controlling the symptoms, maximizing independent mobility, and developing optimal bone mass and muscle strength. Bisphosphonates are the mainstay of pharmacologic fracture-prevention therapy for most forms of OI. The University of the Philippines-Philippine General Hospital Bisphosphonate Treatment Program for OI was started in 2006 by the Clinical Genetics Service. For more than a decade now, the program has been serving more than 50 OI patients. This study evaluated the clinical outcomes of the patients who were included in the program to add to the body of knowledge on Filipino patients with OI. OBJECTIVES: This study sought to determine the clinical outcomes of children with OI on intravenous pamidronate treatment at the Philippine General Hospital (PGH) from January 2010 to December 2018. METHODS: The study utilized a retrospective review of medical records of 24 patients diagnosed with OI on pamidronate therapy seen at the PGH from January 2010 to December 2018. Descriptive statistics were used to summarize the demographic and baseline clinical characteristics of the patients. Median annualized fracture rates before and during treatment were calculated and compared. The patient functional mobility before and during pamidronate infusion was classified accordingly based on the Gross Motor Function Classification System (GMFCS) and were compared. RESULTS: Twenty-four patients, which include seven males and 17 females, with ages at the time of conduct of the study ranging from four years to 11 years, fulfilled the inclusion criteria. There were four patients with OI type I, six with OI type III, 11 with OI type IV and three with OI type V. The annualized long bone fracture rate decreased significantly from a median of 2.0/year (range 1-2.75) to 0.75/year (range 0-1) after more than a year on pamidronate infusion (p < 0.001). There is a note of overall improvement in terms of functional mobility using the 5-point scale of the GMFCS during pamidronate infusion from the baseline. However, the difference is not statistically significant. CONCLUSION Cyclic intravenous pamidronate treatment in young children with moderate-severe OI is well tolerated and associated with reduced fracture frequency with a tendency to improvement of gross functional mobility.
Human ; Osteogenesis Imperfecta ; Bisphosphonate ; Diphosphonates

PURPOSE: This study aims to investigate the efficacy of novel distraction support (DS) in intramedullary nailing treatment for tibial shaft fracture. METHODS: The random controlled trial included adult patients with tibial shaft fractures who were treated with intramedullary nailing at the trauma center between July 2013 and December 2018. Participants were randomly assigned to either control group (n=43) or DS group (n=42) based on whether DS was used during the operation. All surgical procedures were conducted by a single, experienced surgeon. Parameters such as hospital stay, blood loss, operative time, infection, delayed union, and malalignment were recorded for assessment. Shapiro-Wilk test was used to assess normality, and the F test was adopted to measure variance homogeneity. Continuous variables were presented as mean±standard deviation and compared via independent samples t-tests. Categorical variables are expressed as percentages. The Pearson's Chi-squared or Fisher's exact test was used for categorical variables n (%). Two-sided p<0.05 indicated statistical significance. RESULTS: A total of 85 participants were enrolled in the study. All cases achieved acceptable reduction. The operative time was significantly shorter in the DS group than in control group ((75.3±10.5) min vs. (90.4±15.5) min, p<0.001). Additionally, the DS group showed lesser blood loss ((60.1±27.2) mL vs. (85.4±25.4) mL, p<0.001). No significant differences were observed between the 2 groups in terms of hospital stay ((9.4±2.7) days vs. (10.2±3.1) days, p=0.370), infection (3 (7.1%) vs. 2 (4.7%), p=0.978), delayed union (2 (4.8%) vs. 5 (11.6%), p=0.450), and malalignment (3 (7.1%) vs. 5 (11.6%), p=0.713). CONCLUSION The use of DS in intramedullary nailing surgery is effective. The application of this DS system may represent a valuable addition to future clinical practice.
Humans ; Fracture Fixation, Intramedullary/methods* ; Tibial Fractures/surgery* ; Male ; Female ; Adult ; Middle Aged ; Operative Time ; Length of Stay ; Young Adult ; Osteogenesis, Distraction/methods*

BACKGROUND

Osteogenesis imperfecta (OI) is a group of connective tissue disease characterized by propensity to fractures following minimal trauma. OI is a lifelong inheritable disease and currently has no definitive cure. Management goals are directed towards prevention of fractures, controlling the symptoms, maximizing independent mobility, and developing optimal bone mass and muscle strength. Bisphosphonates are the mainstay of pharmacologic fracture-prevention therapy for most forms of OI. The University of the Philippines-Philippine General Hospital Bisphosphonate Treatment Program for OI was started in 2006 by the Clinical Genetics Service. For more than a decade now, the program has been serving more than 50 OI patients. This study evaluated the clinical outcomes of the patients who were included in the program to add to the body of knowledge on Filipino patients with OI.

This study sought to determine the clinical outcomes of children with OI on intravenous pamidronate treatment at the Philippine General Hospital (PGH) from January 2010 to December 2018.

The study utilized a retrospective review of medical records of 24 patients diagnosed with OI on pamidronate therapy seen at the PGH from January 2010 to December 2018. Descriptive statistics were used to summarize the demographic and baseline clinical characteristics of the patients. Median annualized fracture rates before and during treatment were calculated and compared. The patient functional mobility before and during pamidronate infusion was classified accordingly based on the Gross Motor Function Classification System (GMFCS) and were compared.

Twenty-four patients, which include seven males and 17 females, with ages at the time of conduct of the study ranging from four years to 11 years, fulfilled the inclusion criteria. There were four patients with OI type I, six with OI type III, 11 with OI type IV and three with OI type V. The annualized long bone fracture rate decreased significantly from a median of 2.0/year (range 1-2.75) to 0.75/year (range 0-1) after more than a year on pamidronate infusion (pCONCLUSION

Cyclic intravenous pamidronate treatment in young children with moderate-severe OI is well tolerated and associated with reduced fracture frequency with a tendency to improvement of gross functional mobility.

The development of bone in human body and the maintenance of bone mass in adulthood are regulated by a variety of biological factors. Myocyte enhancer factor 2C (MEF2C), as one of the many factors regulating bone tissue development and balance, has been shown to play a key role in bone development and metabolism. However, there is limited systematic analysis on the effects of MEF2C on bone tissue. This article reviews the role of MEF2C in bone development and metabolism. During bone development, MEF2C promotes the development of neural crest cells (NC) into craniofacial cartilage and directly promotes cartilage hypertrophy. In terms of bone metabolism, MEF2C exhibits a differentiated regulatory model across different types of osteocytes, demonstrating both promoting and other potential regulatory effects on bone formation, with its stimulating effect on osteoclasts being determined. In view of the complex roles of MEF2C in bone tissue, this paper also discusses its effects on some bone diseases, providing valuable insights for the physiological study of bone tissue and strategies for the prevention of bone diseases.
Humans ; MEF2 Transcription Factors/physiology* ; Bone and Bones/metabolism* ; Animals ; Bone Development/physiology* ; Osteogenesis/physiology* ; Myogenic Regulatory Factors/physiology*

Tripartite motif-containing (TRIM) family proteins are crucial E3 ubiquitin ligases that have garnered significant attention for their regulatory roles in bone metabolism in recent years. This article reviews the function and regulatory mechanisms of TRIM family proteins in bone metabolism, focusing on their dual roles in bone formation and resorption. It also provides a detailed analysis of signaling pathways and molecular mechanisms by which TRIM family members regulate the activities of osteoblasts and osteoclasts. Research findings suggest that modulating the expression or activity of TRIM family proteins could be beneficial for treating bone diseases such as osteoporosis. This review highlights the molecular mechanisms of TRIM family members in bone physiology and pathology, aiming to provide theoretical basis and scientific guidance for developing novel therapeutic strategies for bone diseases.
Humans ; Ubiquitin-Protein Ligases/physiology* ; Bone and Bones/metabolism* ; Animals ; Tripartite Motif Proteins/physiology* ; Osteoclasts/metabolism* ; Osteoblasts/metabolism* ; Signal Transduction/physiology* ; Osteogenesis/physiology*

Osteoporosis(OP) is a senile bone disease characterized by an imbalance between bone remodeling and bone formation. Targeting pathogenesis of kidney deficiency, spleen deficiency, and blood stasis, Bushen Jianpi Huoxue Decoction has a significant effect on the treatment of OP by tonifying kidney, invigorating spleen, and activating blood circulation. MicroRNA(miRNA) and the anti-apoptotic protein B-cell lymphoma-2-like protein 1(BCL2L1) are closely related to bone cell metabolism. Therefore, in this study, the binding of miR-140-5p to BCL2L1 was detected by dual luciferase assay and polymerase chain reaction(PCR). After silencing or overexpressing miR-140-5p, the apoptosis, autophagy, and osteogenic function of human fetal osteoblast cell line 1.19(HFOB1.19) were observed by flow cytometry and Western blot. Bushen Jianpi Huoxue Decoction-containing serum was prepared by intragastric administration of Bushen Jianpi Huoxue Decoction in rats. Different concentrations of Bushen Jianpi Huoxue Decoction-containing serum were used to treat HFOB1.19 with or without miR-140-5p mimic. The expression of osteogenic proteins in each group was observed, and the role of miR-140-5p/BCL2L1 in apoptosis and autophagy of HFOB1.19 was studied, along with the effect of Bushen Jianpi Huoxue Decoction on these processes. As indicated by the dual luciferase assay, miR-140-5p bound to BCL2L1. Flow cytometry and Western blot showed that miR-140-5p promoted apoptosis and inhibited autophagy in HFOB1.19. After intervention with high, medium, and low doses of Bushen Jianpi Huoxue Decoction-medicated serum, compared with the miR-140-5p NC group, the expression of osteocalcin(OCN), osteopontin(OPN), Runt-related transcription factor 2(RUNX2), and transforming growth factor beta 1(TGF-β1) decreased in the miR-140-5p mimic group, while the expression of bone morphogenetic protein 2(BMP2) showed no significant difference under high-dose intervention. Therefore, miR-140-5p/BCL2L1 can promote apoptosis and inhibit autophagy in HFOB1.19. Bushen Jianpi Huoxue Decoction can affect the osteogenic effect of miR-140-5p through BMP2.
MicroRNAs/metabolism* ; Autophagy/drug effects* ; Apoptosis/drug effects* ; Humans ; Drugs, Chinese Herbal/administration & dosage* ; Animals ; Cell Line ; bcl-X Protein/metabolism* ; Osteoblasts/metabolism* ; Rats ; Osteoporosis/physiopathology* ; Male ; Rats, Sprague-Dawley ; Osteogenesis/drug effects*

This study investigated the mechanism of autophagy in the differentiation processes of MC3T3-E1 cells under osteogenic induction(physiological) and alcohol(AL) intervention(pathological), as well as the mechanism by which icariin(ICA) affected osteogenic differentiation of MC3T3-E1 cells under the pathological condition of AL intervention. Osteogenic mineralized nodule staining confirmed that the cells could differentiate into osteoblasts. After determining the appropriate concentrations of AL and ICA using the CCK-8 assay, seven groups were set up in this study: complete medium(CM) group, osteogenic induction medium(OIM) group, OIM+0.25 mol·L~(-1) AL group, OIM+0.25 mol·L~(-1) AL+1×10~(-8) mol·L~(-1) ICA group, OIM+0.25 mol·L~(-1) AL+1×10~(-7) mol·L~(-1) ICA group, OIM+0.25 mol·L~(-1) AL+1×10~(-6) mol·L~(-1) ICA group, and OIM+0.25 mol·L~(-1) AL+1×10~(-5) mol·L~(-1) ICA group, with a culture period of 7 days. Alkaline phosphatase(ALP) staining was used to detect the relative ALP area. Western blot and RT-qPCR were employed to analyze the expression of osteogenesis-and autophagy-related proteins and mRNAs. Reactive oxygen species(ROS) staining was used to detect ROS levels, and apoptosis was assessed through mitochondrial membrane potential assays. The results showed that ICA increased the relative ALP area that had been reduced by AL intervention. AL down-regulated the expression levels of Wnt family member 1(Wnt1), along with the osteogenesis-related mRNAs Wnt1, β-catenin, Runt-related transcription factor 2(Runx2), osteoprotegerin(OPG), and ALP, thereby inhibiting osteogenic differentiation. ICA up-regulated the expression levels of the osteogenesis-related proteins and mRNAs that had been inhibited by AL, promoting osteogenic differentiation. AL inhibited typical autophagy, while ICA regulated Rubicon to suppress LC3-associated phagocytosis(LAP) and promote typical autophagy. ICA also reduced the ROS levels that were elevated by AL and decreased the apoptosis of osteoblasts induced by AL intervention. In conclusion, ICA can regulate Rubicon to inhibit LAP, promote typical autophagy, eliminate ROS, reduce apoptosis, and ultimately enhance the osteogenic differentiation of MC3T3-E1 cells under the pathological condition of AL intervention by modulating the Wnt/β-catenin signaling pathway.
Autophagy/drug effects* ; Animals ; Osteogenesis/drug effects* ; Mice ; Cell Differentiation/drug effects* ; Osteoblasts/metabolism* ; Ethanol/pharmacology* ; Flavonoids/pharmacology* ; Cell Line ; Reactive Oxygen Species/metabolism* ; Drugs, Chinese Herbal/pharmacology*

Guided by the theory of "the kidney storing essence, governing the bones, and producing marrow", this study explored the mechanism of icariin(ICA) in regulating the osteogenic differentiation of rat bone mesenchymal stem cells(BMSCs) through caveolin-1(Cav1) via in vitro and in vivo experiments, aiming to provide a theoretical basis for the prevention and treatment of postmenopausal osteoporosis with traditional Chinese medicine(TCM). Primary cells were obtained from 4-week-old female SD rats using the whole bone marrow adherent method. Flow cytometry was used to detect the expression of surface markers CD29, CD90, CD11b, and CD45. The potential for osteogenic and adipogenic differentiation was assessed. The effect of ICA on cell viability was determined using the CCK-8 assay, and the impact of ICA on the formation of mineralized nodules was verified by alizarin red staining. A stable Cav1-silenced cell line was constructed using lentivirus. The effect of Cav1 silencing on osteogenic differentiation was observed via alizarin red staining. Western blot analysis was conducted to detect the expression of Cav1, Hippo/TAZ, and osteogenic markers such as Runt-related transcription factor 2(RUNX2) and alkaline phosphatase(ALP). The results showed that primary cells were successfully obtained using the whole bone marrow adherent method, positively expressing surface markers of rat BMSCs and possessing the potential for both osteogenic and adipogenic differentiation. The CCK-8 assay and alizarin red staining results indicated that 1×10~(-7) mol·L~(-1) was the optimal concentration of ICA for intervention in this experiment(P<0.05). During osteogenic induction, ICA inhibited Cav1 expression(P<0.05) while promoting TAZ expression(P<0.05). Alizarin red staining demonstrated that Cav1 silencing significantly promoted the osteogenic differentiation of BMSCs. After ICA intervention, TAZ expression was activated, and the expression of osteogenic markers ALP and RUNX2 was increased. In conclusion, Cav1 silencing significantly promotes the osteogenic differentiation of BMSCs, and ICA promotes this differentiation by inhibiting Cav1 and regulating the Hippo/TAZ signaling pathway.
Animals ; Mesenchymal Stem Cells/metabolism* ; Caveolin 1/genetics* ; Osteogenesis/drug effects* ; Rats, Sprague-Dawley ; Rats ; Cell Differentiation/drug effects* ; Female ; Signal Transduction/drug effects* ; Flavonoids/administration & dosage* ; Protein Serine-Threonine Kinases/genetics* ; Drugs, Chinese Herbal/pharmacology* ; Cells, Cultured ; Humans

This paper aimed to explore the effects of Duzhong Decoction(DZD)-containing serum on the proliferation and osteoblast differentiation of MC3T3-E1 cells through L-type voltage-gated calcium channels(L-VGCCs). L-VGCCs inhibitors, nifedipine and verapamil, were used to block L-VGCCs in osteoblasts. MC3T3-E1 cells were divided into a control group, a low-dose DZD-containing serum(L-DZD) group, a medium-dose DZD-containing serum(M-DZD) group, a high-dose DZD-containing serum(H-DZD) group, a nifedipine group, a H-DZD + nifedipine group, verapamil group, and a H-DZD + verapamil group. The CCK-8 method was used for cell proliferation analysis, alkaline phosphatase(ALP) assay kits for intracellular ALP activity measurement, Western blot for protein expression level in cells, real-time fluorescence quantitative PCR technology for intracellular mRNA expression level determination, fluorescence spectrophotometer for free Ca~(2+) concentration determination in osteoblasts, and alizarin red staining(ARS) for mineralized nodule formation in osteoblasts. The experimental results show that compared to the control group, DZD groups can promote MC3T3-E1 cell proliferation, ALP activity, and mineralized nodule formation, increase intracellular Ca~(2+) concentrations, and upregulate the protein expression of bone morphogenetic protein 2(BMP2), collagen Ⅰ(COL1), α2 subunit protein of L-VGCCs(L-VGCCα2), and the mRNA expression of Runt-related transcription factor 2(RUNX2), and BMP2. After blocking L-VGCCs with nifedipine and verapamil, the intervention effects of DZD-containing serum were inhibited to varying degrees. Both nifedipine and verapamil could inhibit ALP activity, reduce mineralized nodule areas, and downregulate the expression of bone formation-related proteins. Moreover, the effects of DZD-containing serum on increasing MC3T3-E1 cell proliferation, osteoblast differentiation, and Ca~(2+) concentrations, upregulating the mRNA expression of osteoprotegerin(OPG) and protein expression of phosphorylated protein kinase B(p-Akt) and phosphorylated forkhead box protein O1(p-FOXO1), and upregulating phosphatase and tensin homolog(PTEN) expression were reversed by nifedipine. The results indicate that DZD-containing serum can increase the Ca~(2+) concentration in MC3T3-E1 cells to promote bone formation, which may be mediated by L-VGCCs and the PTEN/Akt/FoxO1 signaling pathway, providing a new perspective on the mechanism of DZD in treating osteoporosis.
Animals ; Osteoblasts/metabolism* ; Cell Proliferation/drug effects* ; Cell Differentiation/drug effects* ; Mice ; Drugs, Chinese Herbal/pharmacology* ; Calcium Channels, L-Type/genetics* ; Alkaline Phosphatase/genetics* ; Serum/chemistry* ; Cell Line ; Osteogenesis/drug effects* ; Bone Morphogenetic Protein 2/genetics*

Osteoporotic fractures(OPF) refer to the fractures caused by minor violence in the state of osteoporosis, seriously threatening the life and health of elderly patients. Drug and surgical therapies have limitations such as single targets, diverse adverse reactions, and poor prognosis. Kidney-tonifying traditional Chinese medicine(TCM) has good potential in the treatment of OPF. TCM can promote the healing of OPF by promoting angiogenesis in the early stage of bone healing, promoting osteogenic differentiation of bone marrow mesenchymal stem cells in the stage of bone repair, maintaining the balance of osteogenic and osteoclastic system in the stage of bone remodeling, and regulating the oxidative stress responses throughout the process of OPF healing. TCM can alleviate the pathological state of osteoporosis and promote fracture healing in OPF patients via multiple pathways and targets, demonstrating the advantages and potential of biphasic regulation.
Humans ; Drugs, Chinese Herbal/therapeutic use* ; Osteoporotic Fractures/metabolism* ; Animals ; Fracture Healing/drug effects* ; Medicine, Chinese Traditional ; Kidney/metabolism* ; Osteogenesis/drug effects*