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1.
Nutrients ; 16(5)2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38474792

RESUMO

Colostrum basic protein (CBP) is a trace protein extracted from bovine colostrum. Previous studies have shown that CBP can promote bone cell differentiation and increase bone density. However, the mechanism by which CBP promotes bone activity remains unclear. This study investigated the mechanism of the effect of CBP on bone growth in mice following dietary supplementation of CBP at doses that included 0.015%, 0.15%, 1.5%, and 5%. Compared with mice fed a normal diet, feeding 5% CBP significantly enhanced bone rigidity and improved the microstructure of bone trabeculae. Five-percent CBP intake triggered significant positive regulation of calcium metabolism in the direction of bone calcium accumulation. The expression levels of paracellular calcium transport proteins CLDN2 and CLDN12 were upregulated nearly 1.5-fold by 5% CBP. We conclude that CBP promotes calcium absorption in mice by upregulating the expression of the calcium-transporting paracellular proteins CLND2 and CLND12, thereby increasing bone density and promoting bone growth. Overall, CBP contributes to bone growth by affecting calcium metabolism.


Assuntos
Cálcio , Colostro , Gravidez , Feminino , Animais , Camundongos , Bovinos , Cálcio/metabolismo , Colostro/metabolismo , Cálcio da Dieta/metabolismo , Osso e Ossos/metabolismo , Desenvolvimento Ósseo , Densidade Óssea , Proteínas na Dieta/farmacologia
2.
Physiol Res ; 73(1): 157-172, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38466013

RESUMO

Effects of pre/postnatal 2.45 GHz continuous wave (CW), Wireless-Fidelity (Wi-Fi) Microwave (MW) irradiation on bone have yet to be well defined. The present study used biochemical and histological methods to investigate effects on bone formation and resorption in the serum and the tibia bone tissues of growing rats exposed to MW irradiation during the pre/postnatal period. Six groups were created: one control group and five experimental groups subjected to low-level different electromagnetic fields (EMF) of growing male rats born from pregnant rats. During the experiment, the bodies of all five groups were exposed to 2.45 GHz CW-MW for one hour/day. EMF exposure started after fertilization in the experimental group. When the growing male rats were 45 days old in the postnatal period, the control and five experimental groups' growing male and maternal rats were sacrificed, and their tibia tissues were removed. Maternal rats were not included in the study. No differences were observed between the control and five experimental groups in Receptor Activator Nuclear factor-kB (RANK) biochemical results. In contrast, there was a statistically significant increase in soluble Receptor Activator of Nuclear factor-kB Ligand (sRANKL) and Osteoprotegerin (OPG) for 10 V/m and 15 V/m EMF values. Histologically, changes in the same groups supported biochemical results. These results indicate that pre/postnatal exposure to 2.45 GHz EMF at 10 and 15 V/m potentially affects bone development.


Assuntos
Campos Eletromagnéticos , Micro-Ondas , Gravidez , Feminino , Ratos , Animais , Masculino , Ratos Sprague-Dawley , Micro-Ondas/efeitos adversos , Campos Eletromagnéticos/efeitos adversos , Desenvolvimento Ósseo
3.
JCI Insight ; 9(6)2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38516888

RESUMO

Recently, skeletal stem cells were shown to be present in the epiphyseal growth plate (epiphyseal skeletal stem cells, epSSCs), but their function in connection with linear bone growth remains unknown. Here, we explore the possibility that modulating the number of epSSCs can correct differences in leg length. First, we examined regulation of the number and activity of epSSCs by Hedgehog (Hh) signaling. Both systemic activation of Hh pathway with Smoothened agonist (SAG) and genetic activation of Hh pathway by Patched1 (Ptch1) ablation in Pthrp-creER Ptch1fl/fl tdTomato mice promoted proliferation of epSSCs and clonal enlargement. Transient intra-articular administration of SAG also elevated the number of epSSCs. When SAG-containing beads were implanted into the femoral secondary ossification center of 1 leg of rats, this leg was significantly longer 1 month later than the contralateral leg implanted with vehicle-containing beads, an effect that was even more pronounced 2 and 6 months after implantation. We conclude that Hh signaling activates growth plate epSSCs, which effectively leads to increased longitudinal growth of bones. This opens therapeutic possibilities for the treatment of differences in leg length.


Assuntos
Lâmina de Crescimento , Proteínas Hedgehog , Camundongos , Ratos , Animais , Proteínas Hedgehog/metabolismo , Desenvolvimento Ósseo , Células-Tronco/metabolismo
4.
Aquat Toxicol ; 268: 106834, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38281391

RESUMO

Trifloxystrobin (TRI) is a methacrylate fungicide, and fluopyram (FLU) is a new pyridylethylbenzamide fungicide and nematicide. Both are often detected in water bodies and may be highly toxic to many aquatic organisms. Unfortunately, the aquatic biological risks of single FLU or a mixture of trifloxystrobin and fluopyram have not been reported. In this study, zebrafish was selected as the test organism to investigate the combined toxicity of trifloxystrobin and fluopyram to zebrafish. After zebrafish embryos exposed to three pesticide solutions, Alcian-blue staining, Alizarin-red staining and quantitative PCR (qPCR) were performed. The results indicated that 96h-LC50 of TRI was 0.159 mg·L-1 to zebrafish embryo, which was highly toxic. The 96h-LC50 of FLU to zebrafish embryos was 4.375 mg·L-1, being moderately toxic. The joint toxicity to zebrafish embryos(FLU at 96h-LC50 and TRI at 96h-LC50 in a 1:1 weight ratio to form a series of concentration treatment groups) was antagonistic. Both trifloxystrobin and fluopyram also inhibited the skeletal development of zebrafish and showed to be antagonistic. The results of qPCR indicated upregulations of different genes upon three different treatments. TRI mainly induced Smads up-expression, which may affect the BMP-smads pathway. FLU mainly induced an up-expression of extracellular BMP ligands and type I receptor (Bmpr-1a), which may affect the BMP ligand receptor pathway. The 1:1 mixture (weight ratio) of trifloxystrobin and fluopyram induced a reduction of the genes of extracellular BMP ligand (Smads) and type I receptor (Bmpr1ba), which may down-regulate BMP signaling and thus attenuating cartilage hyperproliferation, hypertrophy and mineralization. The results warren an interest in further studying the effect of the two fungicides in a mixture on zebrafish.


Assuntos
Acetatos , Benzamidas , Fungicidas Industriais , Iminas , Piridinas , Estrobilurinas , Poluentes Químicos da Água , Animais , Peixe-Zebra/metabolismo , Ligantes , Embrião não Mamífero , Poluentes Químicos da Água/toxicidade , Fungicidas Industriais/toxicidade , Desenvolvimento Ósseo
5.
Anat Sci Int ; 99(1): 48-58, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37389734

RESUMO

Pseudoephedrine (PSE) is an agent that is contained in common cold medications. The agent, which is used to treat cold and cough, is the fourth most prescribed drug group in some countries. During pregnancy, expectant mothers use PSE for colds and other reasons. One out of every four expectant mothers use PSE alone or in combination with other medicines for various reasons. This study was aimed to investigate effects of PSE on long bones development in rat during fetal growth. Pregnant rats were divided into five groups: control and four experimental groups (25 mg/kg, 50 mg/kg, 100 mg/kg, 200 mg/kg PSE). Between 1 and 20 days of pregnancy, PSE was given to them by gavage. Weights and heights of fetuses isolated by cesarean on the 21st day were measured. Ossification of femur and humerus was examined by three different methods mentioned earlier. Depending on the dose increase, all morphometric data, ossification rate and bone length of the fetuses were decreased. Besides, it was determined that the amount of Calcium in the bone tissue decreased in the analyzes made with SEM-EDX Analysis. The data obtained from this study reveal that the use of PSE during pregnancy disrupts the existing balance in the bone and negatively affects ossification due to the dose increase. In conclusion, we present descriptive and novel data on the effects of PSE use during pregnancy on the bone development of rat fetal long bones.


Assuntos
Osso e Ossos , Pseudoefedrina , Gravidez , Feminino , Ratos , Animais , Pseudoefedrina/farmacologia , Pseudoefedrina/uso terapêutico , Osteogênese , Feto , Desenvolvimento Ósseo
6.
Curr Opin Endocrinol Diabetes Obes ; 31(1): 53-59, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38010050

RESUMO

PURPOSE OF REVIEW: Bone accrual during childhood and adolescence is critical for the attainment of peak bone mass and is a major contributing factor towards osteoporosis in later life. Bone mass accrual is influenced by nonmodifiable factors, such as genetics, sex, race, ethnicity, and puberty, as well as modifiable factors, such as physical activity and diet. Recent progress in bone imaging has allowed clinicians and researchers to better measure the morphology, density, and strength of the growing skeleton, thereby encompassing key characteristics of peak bone strength. In this review, the patterning of bone accrual and contributors to these changes will be described, as well as new techniques assessing bone mass and strength in pediatric research and clinical settings. RECENT FINDINGS: This review discusses factors influencing peak bone mass attainment and techniques used to assess the human skeleton. SUMMARY: The rate of bone accrual and the magnitude of peak bone mass attainment occurs in specific patterns varying by sex, race, ethnicity, longitudinal growth, and body composition. Physical activity, diet, and nutritional status impact these processes. There is a need for longitudinal studies utilizing novel imaging modalities to unveil factors involved in the attainment and maintenance of peak bone strength.


Assuntos
Desenvolvimento Ósseo , Osteoporose , Criança , Adolescente , Humanos , Densidade Óssea , Osso e Ossos/diagnóstico por imagem , Exercício Físico
7.
Genomics ; 116(1): 110769, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38141931

RESUMO

Estrogen receptor α (ESR1) is involved in E2 signaling and plays a major role in postmenopausal bone loss. However, the molecular network underlying ESR1 has not been explored. We used systems genetics and bioinformatics to identify important genes associated with Esr1 in postmenopausal bone loss. We identified ~2300 Esr1-coexpressed genes in female BXD bone femur, functional analysis of which revealed 'osteoblast signaling' as the most enriched pathway. PPI network led to the identification of 25 'female bone candidates'. The gene-regulatory analysis revealed RUNX2 as a key TF. ANKRD1 and RUNX2 were significantly different between osteoporosis patients and healthy controls. Sp7, Col1a1 and Pth1r correlated with multiple femur bone phenotypes in BXD mice. miR-3121-3p targeted Csf1, Ankrd1, Sp7 and Runx2. ß-estradiol treatment markedly increased the expression of these candidates in mouse osteoblast. Our study revealed that Esr1-correlated genes Ankrd1, Runx2, Csf1 and Sp7 may play important roles in female bone development.


Assuntos
Osteoporose Pós-Menopausa , Osteoporose , Humanos , Feminino , Camundongos , Animais , Osteoporose Pós-Menopausa/genética , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Osso e Ossos/metabolismo , Osteoporose/genética , Desenvolvimento Ósseo/genética , Diferenciação Celular
8.
Dev Cell ; 59(2): 211-227.e5, 2024 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-38141609

RESUMO

Fetal bone development occurs through the conversion of avascular cartilage to vascularized bone at the growth plate. This requires coordinated mobilization of osteoblast precursors with blood vessels. In adult bone, vessel-adjacent osteoblast precursors are maintained by mechanical stimuli; however, the mechanisms by which these cells mobilize and respond to mechanical cues during embryonic development are unknown. Here, we show that the mechanoresponsive transcriptional regulators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) spatially couple osteoblast precursor mobilization to angiogenesis, regulate vascular morphogenesis to control cartilage remodeling, and mediate mechanoregulation of embryonic murine osteogenesis. Mechanistically, YAP and TAZ regulate a subset of osteoblast-lineage cells, identified by single-cell RNA sequencing as vessel-associated osteoblast precursors, which regulate transcriptional programs that direct blood vessel invasion through collagen-integrin interactions and Cxcl12. Functionally, in 3D human cell co-culture, CXCL12 treatment rescues angiogenesis impaired by stromal cell YAP/TAZ depletion. Together, these data establish functions of the vessel-associated osteoblast precursors in bone development.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Transativadores , Animais , Humanos , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Desenvolvimento Ósseo , Morfogênese , Osteoblastos/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Proteínas de Sinalização YAP
9.
Microsc Res Tech ; 87(1): 95-104, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37705325

RESUMO

Radiation has been widely used in many business sectors over the last century. Our study investigated the possible teratogenic effects of radiation on the bones of rat fetuses and the protective effect of melatonin against these effects. In this study, 15 pregnant female Wistar albino rats were used. These rats were divided into four groups: the control group, melatonin group (10 mg/kg/day), radiation group (0.5 gray), radiation (0.5 gray) + melatonin group (10 mg/kg/day), and sham group (1 mm hanks/day). The skeletal system development of fetuses was examined with double skeletal and scanning electron microscope (SEM), histopathological methods. In our study, fetal weight, placental weight, and fetal morphometric values were found to be statistically significantly decreased in the radiation group compared to the control group (p < .05). In immünohistochemistry (IHC) analysis, alkaline phosphatase, and tartrate-resistant acid phosphatase) concentrations were found to be significantly lower in the radiation group compared to the other groups. In the SEM analysis, it was observed that the amount of calcium and sodium decreased when the radiation group was compared with the other groups. As a result, when exposed to ionizing radiation during pregnancy, melatonin has a protective feature against the negative effects of radiation on the bone development of fetuses. RESEARCH HIGHLIGHTS: In our study, fetuses obtained from pregnant rats exposed to ionizing radiation were examined. In this study, the effect of melatonin on bone development in fetuses exposed to gray ionizing radiation was investigated. There are few studies on our subject in the literature. We believe that our findings will contribute to other planned studies.


Assuntos
Melatonina , Ratos , Feminino , Gravidez , Animais , Melatonina/farmacologia , Ratos Wistar , Placenta , Radiação Ionizante , Feto , Desenvolvimento Ósseo
10.
Int J Mol Sci ; 24(23)2023 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-38068932

RESUMO

Approximately 80% of children with short stature are classified as having Idiopathic Short Stature (ISS). While growth hormone (GH) treatment received FDA approval in the United States in 2003, its long-term impact on final height remains debated. Other treatments, like aromatase inhibitors, metformin, and insulin-like growth factor-1 (IGF-1), have been explored, but there is no established standard treatment for ISS. In South Korea and other Asian countries, East Asian Traditional Medicine (EATM) is sometimes employed by parents to potentially enhance their children's height growth, often involving herbal medicines. One such product, Astragalus membranaceus extract mixture HT042, claims to promote height growth in children and has gained approval from the Korean Food and Drug Administration (KFDA). Research suggests that HT042 supplementation can increase height growth in children without skeletal maturation, possibly by elevating serum IGF-1 and IGF-binding protein-3 levels. Preclinical studies also indicate the potential benefits of natural products, including of EATM therapies for ISS. The purpose of this review is to offer an overview of bone growth factors related to ISS and to investigate the potential of natural products, including herbal preparations, as alternative treatments for managing ISS symptoms, based on their known efficacy in in vivo studies.


Assuntos
Produtos Biológicos , Nanismo , Hormônio do Crescimento Humano , Criança , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Transtornos do Crescimento/tratamento farmacológico , Desenvolvimento Ósseo , Hormônio do Crescimento Humano/farmacologia
11.
Front Endocrinol (Lausanne) ; 14: 1258313, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38152138

RESUMO

Very tall people attract much attention and represent a clinically and genetically heterogenous group of individuals. Identifying the genetic etiology can provide important insights into the molecular mechanisms regulating linear growth. We studied a three-generation pedigree with five isolated (non-syndromic) tall members and one individual with normal stature by whole exome sequencing; the tallest man had a height of 211 cm. Six heterozygous gene variants predicted as damaging were shared among the four genetically related tall individuals and not present in a family member with normal height. To gain insight into the putative role of these candidate genes in bone growth, we assessed the transcriptome of murine growth plate by microarray and RNA Seq. Two (Ift140, Nav2) of the six genes were well-expressed in the growth plate. Nav2 (p-value 1.91E-62) as well as Ift140 (p-value of 2.98E-06) showed significant downregulation of gene expression between the proliferative and hypertrophic zone, suggesting that these genes may be involved in the regulation of chondrocyte proliferation and/or hypertrophic differentiation. IFT140, NAV2 and SCAF11 have also significantly associated with height in GWAS studies. Pathway and network analysis indicated functional connections between IFT140, NAV2 and SCAF11 and previously associated (tall) stature genes. Knockout of the all-trans retinoic acid responsive gene, neuron navigator 2 NAV2, in Xenopus supports its functional role as a growth promotor. Collectively, our data expand the spectrum of genes with a putative role in tall stature phenotypes and, among other genes, highlight NAV2 as an interesting gene to this phenotype.


Assuntos
Estatura , DNA Helicases , Animais , Humanos , Masculino , Camundongos , Desenvolvimento Ósseo , Lâmina de Crescimento , Tretinoína , Estatura/genética , DNA Helicases/genética
12.
J Anim Sci ; 1012023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-37933958

RESUMO

This study aimed to investigate the effects of diets supplemented with 25-hydroxycholecalciferol [25-(OH)D3] and additional vitamin E on growth performance, antioxidant capacity, bone development, and carcass characteristics at different stocking densities on commercial broiler farms. A total of 118,800 one-day-old Arbor Acres broilers were assigned to a 2 × 2 factorial treatment consisting of two dietary vitamin levels (5,500 IU vitamin D3 and 60 IU vitamin E: normal diet, using half 25-(OH)D3 as a source of vitamin D3 and an additional 60 IU of vitamin E: 25-(OH)D3+VE diet) and two stocking densities (high density of 20 chickens/m2: HD and 16 chickens/m2: LD). The experiment lasted for 42 d. The results showed that high-density stocking negatively affected the growth performance of broilers during the first four weeks, whereas the vitamin diet treatment significantly improved the feed conversion ratios (FCR) during the last 2 wk. Vitamin diets increased catalase at 14 and 42 d, and the glutathione peroxidase (GSH-px) levels at 42 d in high-density-stocked broilers. The interaction showed that serum vitamin E levels were significantly improved at 28 d of age in high-density-stocked broilers as a result of the vitamin diets. Stocking density and dietary treatments were found to significantly affect bone development, with the vitamin diet significantly increasing metatarsal length and femoral bone strength in broilers from high-density stocking density at 28 d of age. High stocking density increased the proportion of leg muscles and meat yield per square meter. In general, 25-(OH)D3 and additional vitamin E suppressed oxidative stress and ameliorated the negative effects of high-density stocking on bone development in a commercial chicken farm setting. Vitamin diets improved the FCR of broilers, while high-density stocking resulted in better economic outcomes.


High-density stocking is often associated with animal welfare risks in broilers, mainly in terms of oxidative stress and bone development. Nevertheless, farming at too low a density remains for the most part economically unviable. Modulation of antioxidant capacity and bone development by nutritional strategies in high-density-farmed broilers has proven an effective tool in developing countries. Therefore, the present study investigated the effects of applying diets with a higher biological potency of vitamin D3 25-hydroxycholecalciferol [25-(OH)D3] and a higher concentration of vitamin E on broiler production performance, antioxidant capacity and meat production performance at different densities of stocking under commercial farming conditions. The results indicated that the vitamin dietary treatments suppressed oxidative stress and ameliorated the negative effects of high-density farming on bone development.


Assuntos
Calcifediol , Galinhas , Animais , Calcifediol/farmacologia , Galinhas/fisiologia , Antioxidantes , Vitamina E/farmacologia , Dieta/veterinária , Suplementos Nutricionais , Vitaminas/farmacologia , Colecalciferol , Desenvolvimento Ósseo , Ração Animal/análise
13.
Curr Osteoporos Rep ; 21(6): 815-824, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37837512

RESUMO

PURPOSE OF REVIEW: Here, we discuss the origin of chondrocytes, their destiny, and their plasticity in relationship to bone growth, articulation, and formation of the trabeculae. We also consider these processes from a biological, clinical, and evolutionary perspective. RECENT FINDINGS: Chondrocytes, which provide the template for the formation of most bones, are responsible for skeletal growth and articulation during postnatal life. In recent years our understanding of the fate of these cells has changed dramatically. Current evidence indicates a paradoxical situation during skeletogenesis, with some cells of mesenchymal condensation differentiating directly into osteoblasts, whereas others of the same kind give rise to highly similar osteoblasts via a complex process of differentiation involving several chondrocyte intermediates. The situation becomes even more paradoxical during postnatal growth when stem cells in the growth plate produce differentiated, functional progenies, which thereafter presumably dedifferentiate into another type of stem cell. Such a remarkable transition from one cell type to another under postnatal physiological conditions provides a fascinating example of cellular plasticity that may have valuable clinical implications.


Assuntos
Plasticidade Celular , Condrócitos , Humanos , Osteogênese/fisiologia , Desenvolvimento Ósseo/fisiologia , Osso e Ossos , Osteoblastos/metabolismo , Lâmina de Crescimento/metabolismo , Diferenciação Celular/fisiologia
14.
Hum Exp Toxicol ; 42: 9603271231210970, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37903444

RESUMO

The use of Methylphenidate (MP) can have adverse effects on bone growth and mineralization. This study aimed to investigate the underlying pathophysiology of MP-induced skeletal deficits in growing rats using stereological and immunohistochemical methods. Male rats, aged 4 weeks, were orally treated with MP through an 8-h/day water drinking protocol. The rats (n=30) were randomly divided into three groups: MP-High Dose (30/60 mg/kg/day MP), MP-Low Dose (4/10 mg/kg/day MP), and control (water only). After 13 weeks, the femoral bones were assessed using calliper measurements, dual-energy X-ray absorptiometry, and biomechanical evaluation. The total femur volume, cartilage volume, growth zone volume, and volume fractions were determined using the Cavalieri method. Immunohistochemical analyses were conducted using alkaline phosphatase and anti-calpain antibody staining. Rats exposed to MP exhibited significant reductions in weight gain, femoral growth, bone mineralization, and biomechanical integrity compared to the control group. The total femoral volume of MP-treated rats was significantly lower than that of the control group. The MP-High Dose group showed significantly higher ratios of total cartilage volume/total femoral volume and total growth zone volume/total femoral volume than the other groups. Immunohistochemical evaluation of the growth plate revealed reduced osteoblastic activity and decreased intracellular calcium deposition with chronic MP exposure. The possible mechanism of MP-induced skeletal growth retardation may involve the inhibition of intracellular calcium deposition in chondrocytes of the hypertrophic zone in the growth plate. In this way, MP may hinder the differentiation of cartilage tissue from bone tissue, resulting in reduced bone growth and mineralization.


Assuntos
Metilfenidato , Animais , Masculino , Ratos , Desenvolvimento Ósseo , Cálcio , Fêmur , Metilfenidato/toxicidade , Água
15.
J Med Food ; 26(11): 809-819, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37862561

RESUMO

Previous studies have reported that collagen tripeptide (CTP) derived from collagen hydrolysate has various beneficial effects on health by protecting against skin aging and improving bone formation and cartilage regeneration. Collagen-Tripep20TM (CTP20), which is a low-molecular-weight CTP derived from fish skin, contains a bioactive CTP, Gly-Pro-Hyp >3.2% with a tripeptide content >20%. Herein, we investigated the osteogenic effects and mechanisms of CTP20 (<500 Da) on MG-63 osteoblast-like cells and SW1353 chondrocytes. And we measured promoting ratio of the longitudinal bone growth in childhood rats. First, CTP20 at 100 µg/mL elevated the proliferation (15.0% and 28.2%), alkaline phosphatase activity (29.3% and 32.0%), collagen synthesis (1.25- and 1.14-fold), and calcium deposition (1.18- and 1.15-fold) in MG-63 cells and SW1353, respectively. In addition, we found that CTP20 could promote the longitudinal growth and height of the growth plate of the tibia in childhood rats. CTP20 enhanced the protein expression of insulin-like growth factor-1 (IGF-1) in MG-63 and SW1353 cells, and in the growth plate of childhood rats, along with Janus Kinase 2, and signal transducer and activator of transcription 5 activation in MG-63 and SW1353 cells. CTP20 also elevated the expression levels of bone morphogenetic proteins (BMPs) in MG-63 and SW1353 cells and in the growth plates of childhood rats. These results indicate that CTP20 may promote the endochondral ossification and longitudinal bone growth, through enhancing of IGF-1 and BMPs. (Clinical Trial Registration number: smecae 19-09-01).


Assuntos
Desenvolvimento Ósseo , Fator de Crescimento Insulin-Like I , Humanos , Ratos , Animais , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like I/farmacologia , Proteínas Morfogenéticas Ósseas/metabolismo , Proteínas Morfogenéticas Ósseas/farmacologia , Osteogênese , Colágeno/farmacologia
16.
Physiol Rep ; 11(19): e15837, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37813559

RESUMO

The peripartal period is marked by alterations in calcium metabolism to accommodate for embryonic skeletal mineralization and support bone development of offspring in early life, and serotonin plays a critical role in modulating peripartal bone remodeling. Selective serotonin reuptake inhibitors (SSRIs) are commonly used as first-line treatment for psychiatric illness during pregnancy and the postpartum period and considered safe for maternal use during this time frame. In order to evaluate the effect of peripartal alterations of the serotonergic system on maternal skeletal physiology, we treated dams with the SSRI fluoxetine during gestation only, lactation only, or during the entire peripartal period. Overall, we found a low dose of fluoxetine during gestation only had minimal impacts on maternal bone at weaning, but there were implications on maternal skeleton at weaning when dams were exposed during lactation only or during the entire peripartal period. We found that these effects were differential between female mice dosed lactationally or peripartally, and there were also impacts on maternal mammary gland at weaning in both of these groups. Though SSRIs are largely considered safe maternally during the peripartal period, this study raises the question whether safety of SSRIs, specifically fluoxetine, during the peripartal period should be reevaluated.


Assuntos
Fluoxetina , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Camundongos , Animais , Feminino , Humanos , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Lactação , Osso e Ossos/metabolismo , Desenvolvimento Ósseo , Efeitos Tardios da Exposição Pré-Natal/metabolismo
17.
PLoS One ; 18(10): e0282937, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37819881

RESUMO

Preterm human infants often show periodic breathing (PB) or apnea of prematurity (AOP), breathing patterns which are accompanied by intermittent hypoxia (IH). We examined cause-effect relationships between transient IH and reduced facial bone growth using a rat model. Neonatal pups from 14 timed pregnant Sprague-Dawley rats were randomly assigned to an IH condition, with oxygen altering between 10% and 21% every 4 min for 1 h immediately after birth, or to a litter-matched control group. The IH pups were compared with their age- and sex-matched control groups in body weight (WT), size of facial bones and nor-epinephrine (NE) levels in blood at 3, 4, and 5-weeks. Markedly increased activity of osteoclasts in sub-condylar regions of 3-week-old IH-treated animals appeared, as well as increased numbers of sympathetic nerve endings in the same region of tissue sections. Male IH-pups showed significantly higher levels of NE levels in sera at 3, 4 as well as 5-week-old time points. NE levels in 4- and-5-week-old female pups did not differ significantly. Intercondylar Width, Mandible Length and Intermolar Width measures consistently declined after IH insults in 3- and 4-week-old male as well as female animals. Three-week-old male IH-pups only showed a significantly reduced (p < 0.05) body weight compared to those of 3-week controls. However, female IH-pups were heavier than age-matched controls at all 3 time-points. Trabecular bone configuration, size of facial bones, and metabolism are disturbed after an IH challenge 1 h immediately after birth. The findings raise the possibility that IH, introduced by breathing patterns such as PB or AOP, induce significantly impaired bone development and metabolic changes in human newborns. The enhanced NE outflow from IH exposure may serve a major role in deficient bone growth, and may affect bone and other tissue influenced by that elevation.


Assuntos
Hipóxia , Roedores , Humanos , Recém-Nascido , Gravidez , Ratos , Animais , Masculino , Feminino , Ratos Sprague-Dawley , Animais Recém-Nascidos , Peso Corporal , Ossos Faciais , Desenvolvimento Ósseo
18.
J Bone Miner Res ; 38(11): 1718-1730, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37718532

RESUMO

SNARE proteins comprise a conserved protein family responsible for catalyzing membrane fusion during vesicle traffic. Syntaxin18 (STX18) is a poorly characterized endoplasmic reticulum (ER)-resident t-SNARE. Recently, together with TANGO1 and SLY1, its involvement was shown in ER to Golgi transport of collagen II during chondrogenesis. We report a fetus with a severe osteochondrodysplasia in whom we identified a homozygous substitution of the highly conserved p.Arg10 to Pro of STX18. CRISPR/Cas9-mediated Stx18 deficiency in zebrafish reveals a crucial role for Stx18 in cartilage and bone development. Furthermore, increased expression of multiple components of the Stx18 SNARE complex and of COPI and COPII proteins suggests that Stx18 deficiency impairs antero- and retrograde vesicular transport in the crispant stx18 zebrafish. Taken together, our studies highlight a new candidate gene for a recessive form of osteochondrodysplasia, thereby possibly broadening the SNAREopathy phenotypic spectrum and opening new doors toward future research avenues. © 2023 American Society for Bone and Mineral Research (ASBMR).


Assuntos
Osteocondrodisplasias , Peixe-Zebra , Animais , Humanos , Proteínas Qa-SNARE/genética , Proteínas Qa-SNARE/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Osteocondrodisplasias/metabolismo , Complexo de Golgi/metabolismo , Cartilagem/metabolismo , Desenvolvimento Ósseo , Transporte Proteico
19.
Sci Rep ; 13(1): 15170, 2023 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-37704707

RESUMO

This study is the first to investigate the process of osteoclast (OCL) differentiation, its potential functions, and the associated mRNA and signalling pathways in embryonic palatal bone. Our findings suggest that OCLs are involved in bone remodelling, bone marrow cavity formation, and blood vessel formation in embryonic palatal bone. We observed TRAP-positive OCLs at embryonic day 16.5 (E16.5), E17.5, and E18.5 at the palatal process of the palate (PPP) and posterior and anterior parts of the palatal process of the maxilla (PPMXP and PPMXA, respectively), with OCL differentiation starting 2 days prior to TRAP positivity. By comparing the key periods of OCL differentiation between PPMX and PPP (E14.5, E15.5, and E16.5) using RNA-seq data of the palates, we found that the PI3K-AKT and MAPK signalling pathways were sequentially enriched, which may play critical roles in OCL survival and differentiation. Csf1r, Tnfrsff11a, Ctsk, Fos, Tyrobp, Fcgr3, and Spi1 were significantly upregulated, while Pik3r3, Tgfbr1, and Mapk3k7 were significantly downregulated, in both PPMX and PPP. Interestingly, Tnfrsff11b was upregulated in PPMX but downregulated in PPP, which may regulate the timing of OCL appearance. These results contribute to the limited knowledge regarding mRNA-specific steps in OCL differentiation in the embryonic palatal bone.


Assuntos
Osteoclastos , Fosfatidilinositol 3-Quinases , Animais , Camundongos , Transdução de Sinais , Desenvolvimento Ósseo/genética , RNA Mensageiro/genética
20.
J Transl Med ; 21(1): 668, 2023 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-37759285

RESUMO

Osteoporosis is a systemic bone disease characterized by low bone mass, microarchitectural deterioration, increased bone fragility, and fracture susceptibility. It commonly occurs in older people, especially postmenopausal women. As global ageing increases, osteoporosis has become a global burden. There are a number of medications available for the treatment of osteoporosis, categorized as anabolic and anti-resorptive. Unfortunately, there is no drugs which have dual influence on bone, while all drugs have limitations and adverse events. Some serious adverse events include jaw osteonecrosis and atypical femoral fracture. Recently, a novel medication has appeared that challenges this pattern. Romosozumab is a novel drug monoclonal antibody to sclerostin encoded by the SOST gene. It has been used in Japan since 2019 and has achieved promising results in treating osteoporosis. However, it is also accompanied by some controversy. While it promotes rapid bone growth, it may cause serious adverse events such as cardiovascular diseases. There has been scepticism about the drug since its inception. Therefore, the present review comprehensively covered romosozumab from its inception to its clinical application, from animal studies to human studies, and from safety to cost. We hope to provide a better understanding of romosozumab for its clinical application.


Assuntos
Osteoporose , Animais , Feminino , Humanos , Idoso , Osteoporose/tratamento farmacológico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Envelhecimento , Desenvolvimento Ósseo
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