RESUMO
We previously described a new osteogenic growth factor, osteolectin/Clec11a, which is required for the maintenance of skeletal bone mass during adulthood. Osteolectin binds to Integrin α11 (Itga11), promoting Wnt pathway activation and osteogenic differentiation by leptin receptor+ (LepR+) stromal cells in the bone marrow. Parathyroid hormone (PTH) and sclerostin inhibitor (SOSTi) are bone anabolic agents that are administered to patients with osteoporosis. Here we tested whether osteolectin mediates the effects of PTH or SOSTi on bone formation. We discovered that PTH promoted Osteolectin expression by bone marrow stromal cells within hours of administration and that PTH treatment increased serum osteolectin levels in mice and humans. Osteolectin deficiency in mice attenuated Wnt pathway activation by PTH in bone marrow stromal cells and reduced the osteogenic response to PTH in vitro and in vivo. In contrast, SOSTi did not affect serum osteolectin levels and osteolectin was not required for SOSTi-induced bone formation. Combined administration of osteolectin and PTH, but not osteolectin and SOSTi, additively increased bone volume. PTH thus promotes osteolectin expression and osteolectin mediates part of the effect of PTH on bone formation.
Assuntos
Fatores de Crescimento de Células Hematopoéticas/metabolismo , Lectinas Tipo C/metabolismo , Osteogênese/efeitos dos fármacos , Hormônio Paratireóideo/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Osso Esponjoso/efeitos dos fármacos , Osso Esponjoso/patologia , Feminino , Fatores de Crescimento de Células Hematopoéticas/sangue , Fatores de Crescimento de Células Hematopoéticas/deficiência , Humanos , Lectinas Tipo C/sangue , Lectinas Tipo C/deficiência , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Osteoporose/sangue , Pré-Menopausa/sangue , Via de Sinalização Wnt/efeitos dos fármacosRESUMO
OBJECTIVE: It is unclear if different factors influence osteoarthritis (OA) progression and degenerative changes characterising OA disease in hip and knee. We investigated the difference between hip OA and knee OA at the subchondral bone (SCB) tissue and cellular level, relative to the degree of cartilage degeneration. DESIGN: Bone samples were collected from 11 patients (aged 70.4 ± 10.7years) undergoing knee arthroplasty and 8 patients (aged 62.3 ± 13.4years) undergoing hip arthroplasty surgery. Trabecular bone microstructure, osteocyte-lacunar network, and bone matrix vascularity were evaluated using synchrotron micro-CT imaging. Additionally, osteocyte density, viability, and connectivity were determined histologically. RESULTS: The associations between severe cartilage degeneration and increase of bone volume fraction (%) [- 8.7, 95% CI (-14.1, -3.4)], trabecular number (#/mm) [- 1.5, 95% CI (-0.8, -2.3)], osteocyte lacunar density (#/mm3) [4714.9; 95% CI (2079.1, 7350.6)] and decrease of trabecular separation (mm) [- 0.07, 95% CI (0.02, 0.1)] were found in both knee and hip OA. When compared to knee OA, hip OA was characterised by larger (µm3) but less spheric osteocyte lacunae [47.3; 95% CI (11.2, 83.4), - 0.04; 95% CI (-0.06, -0.02), respectively], lower vascular canal density (#/mm3) [- 22.8; 95% CI (-35.4, -10.3)], lower osteocyte cell density (#/mm2) [- 84.2; 95% CI (-102.5, -67.4)], and less senescent (#/mm2) but more apoptotic osteocytes (%) [- 2.4; 95% CI (-3.6, -1.2), 24.9; 95% CI (17.7, 32.1)], respectively. CONCLUSION: SCB from hip OA and knee OA exhibits different characteristics at the tissue and cellular levels, suggesting different mechanisms of OA progression in different joints.
Assuntos
Cartilagem Articular , Osteoartrite do Quadril , Osteoartrite do Joelho , Humanos , Osteoartrite do Quadril/diagnóstico por imagem , Osteoartrite do Quadril/patologia , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/patologia , Síncrotrons , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/patologia , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/patologia , Microtomografia por Raio-X/métodos , Cartilagem Articular/diagnóstico por imagem , Cartilagem Articular/patologiaRESUMO
The nuclear lamina protein lamin A/C is a key component of the nuclear envelope. Mutations in the lamin A/C gene (LMNA) are identified in patients with various types of laminopathy-containing diseases, which have features of accelerated aging and osteoporosis. However, the underlying mechanisms for laminopathy-associated osteoporosis remain largely unclear. Here, we provide evidence that loss of lamin A/C in skeletal muscles, but not osteoblast (OB)-lineage cells, results in not only muscle aging-like deficit but also trabecular bone loss, a feature of osteoporosis. The latter is due in large part to elevated bone resorption. Further cellular studies show an increase of osteoclast (OC) differentiation in cocultures of bone marrow macrophages/monocytes (BMMs) and OBs after treatment with the conditioned medium (CM) from lamin A/C-deficient muscle cells. Antibody array screening analysis of the CM proteins identifies interleukin (IL)-6, whose expression is markedly increased in lamin A/C-deficient muscles. Inhibition of IL-6 by its blocking antibody in BMM-OB cocultures diminishes the increase of osteoclastogenesis. Knockout (KO) of IL-6 in muscle lamin A/C-KO mice diminishes the deficits in trabecular bone mass but not muscle. Further mechanistic studies reveal an elevation of cellular senescence marked by senescence-associated beta-galactosidase (SA-ß-gal), p16Ink4a, and p53 in lamin A/C-deficient muscles and C2C12 muscle cells, and the p16Ink4a may induce senescence-associated secretory phenotype (SASP) and IL-6 expression. Taken together, these results suggest a critical role for skeletal muscle lamin A/C to prevent cellular senescence, IL-6 expression, hyperosteoclastogenesis, and trabecular bone loss, uncovering a pathological mechanism underlying the link between muscle aging/senescence and osteoporosis.
Assuntos
Envelhecimento/patologia , Lamina Tipo A/deficiência , Músculo Esquelético/patologia , Osteoporose/patologia , Animais , Anticorpos Bloqueadores/farmacologia , Fenômenos Biomecânicos , Reabsorção Óssea/complicações , Reabsorção Óssea/patologia , Osso Esponjoso/efeitos dos fármacos , Osso Esponjoso/patologia , Diferenciação Celular/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Interleucina-6/metabolismo , Camundongos Knockout , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteoclastos/patologia , Osteogênese/efeitos dos fármacos , Osteoporose/sangue , FenótipoRESUMO
Irisin is a peptide secreted by skeletal muscle that plays a major role in bone metabolism. Experiments in mouse models have shown that administration of recombinant irisin prevents disuse-induced bone loss. In this study, we aimed to evaluate the effects of irisin treatment for the prevention of bone loss in the ovariectomized (Ovx) mouse, the animal model commonly used to investigate osteoporosis caused by estrogen deficiency. Micro-Ct analysis conducted on Sham mice (Sham-veh) and Ovx mice treated with vehicle (Ovx-veh) or recombinant irisin (Ovx-irisn) showed bone volume fraction (BV/TV) decreases in femurs (Ovx-veh 1.39± 0.71 vs. Sham-veh 2.84 ± 1.23; p = 0.02) and tibia at both proximal condyles (Ovx-veh 1.97 ± 0.68 vs. Sham-veh 3.48 ± 1.26; p = 0.03) and the subchondral plate (Ovx-veh 6.33 ± 0.36 vs. Sham-veh 8.18 ± 0.41; p = 0.01), which were prevented by treatment with a weekly dose of irisin for 4 weeks. Moreover, histological analysis of trabecular bone showed that irisin increased the number of active osteoblasts per bone perimeter (Ovx-irisin 32.3 ± 3.9 vs. Ovx-veh 23.5 ± 3.6; p = 0.01), while decreasing osteoclasts (Ovx-irisin 7.6 ± 2.4 vs. Ovx-veh 12.9 ± 3.04; p = 0.05). The possible mechanism by which irisin enhances osteoblast activity in Ovx mice is upregulation of the transcription factor Atf4, one of the key markers of osteoblast differentiation, and osteoprotegerin, thereby inhibiting osteoclast formation.
Assuntos
Doenças Ósseas Metabólicas , Osteoporose , Camundongos , Animais , Feminino , Humanos , Fibronectinas/farmacologia , Osso Esponjoso/patologia , Osteoporose/patologia , Modelos Animais de Doenças , Osteoblastos/patologia , Ovariectomia/efeitos adversos , Densidade ÓsseaRESUMO
OBJECTIVES: To analyse the microstructural changes of subchondral trabecular bone in patients with osteonecrosis of the femoral head (ONFH) using multi-detector row computed tomography (MDCT). METHODS: We retrospectively investigated 76 hips in 50 patients diagnosed with ONFH between 2017 and 2021. Groups 1, 2, 3, and 4 comprised hips without ONFH, ONFH without femoral head collapse (FHC), ONFH with mild collapse (<2 mm), and ONFH with severe collapse (>2 mm), respectively. All patients underwent MDCT, and the subchondral trabecular bone microstructure was assessed. Regions of interests were set at the lateral boundary of the femoral head necrotic lesion and centre of the acetabular weight-bearing portion. RESULTS: In both the femoral head and the acetabular regions, there were significant differences in Groups 2 and 3 compared to Group 1, with increased volumetric bone mineral density and apparent bone volume fraction, and more plate-like with increased connectivity, indicating that osteosclerotic changes were occurring. CONCLUSIONS: In both the femoral head and the acetabular regions, osteosclerotic changes of subchondral trabecular bone microstructure were present before FHC.
Assuntos
Osso Esponjoso , Necrose da Cabeça do Fêmur , Humanos , Estudos Retrospectivos , Osso Esponjoso/patologia , Cabeça do Fêmur , TomografiaRESUMO
Osteocytes are master regulators of skeletal homeostasis. However, little is known about the molecular mechanism of their differentiation. Epigenetic regulations, especially H3K27me3 modification, play critical roles in cell differentiation. Here, we found that H3K27me3 in the loci of osteocyte-expressing genes decreased during osteocyte differentiation and that H3K27me3 demethylase, Utx, was bound to the loci of those genes. To investigate the physiological functions of Utx in vivo, we generated late osteoblast-to-osteocyte specific Utx knockout mice using Dmp1-cre mice (UtxΔOcy/ΔOcy). Micro CT analyses showed that UtxΔOcy/ΔOcy displayed osteopenic phenotypes with lower bone volume and trabecular number, and greater trabecular separation. Bone histomorphometric analysis showed that bone mineralization and formation were significantly lower in UtxΔOcy/ΔOcy. Furthermore, Dmp1 expression and the number of osteocytes were significantly decreased in UtxΔOcy/ΔOcy. These results suggest that Utx in Dmp1-expressing osteoblast/osteocyte positively regulates osteoblast-to-osteocyte differentiation through H3K27me3 modifications in osteocyte genes. Our results provide new insight into the molecular mechanism of osteocyte differentiation.
Assuntos
Diferenciação Celular , Histona Desmetilases/metabolismo , Histonas/metabolismo , Lisina/metabolismo , Osteoblastos/citologia , Osteócitos/citologia , Animais , Sequência de Bases , Doenças Ósseas Metabólicas/genética , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/patologia , Contagem de Células , Diferenciação Celular/genética , Regulação para Baixo/genética , Epigenoma , Loci Gênicos , Histona Desmetilases/deficiência , Metilação , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoblastos/metabolismo , Osteócitos/metabolismo , Fenótipo , Processamento de Proteína Pós-Traducional , Transcriptoma/genéticaRESUMO
OBJECTIVE: This study aimed to investigate the abnormal subchondral trabecular bone (STB) remodeling in knee osteoarthritis (OA) under the influence of knee alignment [hip-knee-ankle (HKA) angle]. DESIGN: Forty-one patients with knee OA underwent radiographic examination before total knee arthroplasty (TKA) for the measurement of HKA angle. Tibial plateau specimens obtained during TKA were used for histomorphometric analyses to assess STB remodeling and cartilage degradation. Tartrate-resistant acidic phosphatase (TRAP) staining was used to test osteoclast activity. Osterix, osteocalcin, and sclerostin expression in the STB were determined using immunohistochemistry. RESULTS: The interaction between HKA angle and side (medial vs lateral of tibial plateau) was the main significant influence factor for STB remodeling and microstructure. The STB with the deviation of the knee alignment was accompanied by obvious abnormal bone remodeling and microstructural sclerosis. Bone volume fraction (BV/TV) was the only significant influence factor for OARSI score, the larger the BV/TV of STB, the higher the OARSI score of cartilage. Moreover, the tibial plateau affected by alignment had more TRAP + osteoclasts, Osterix + osteoprogenitors, and osteocalcin + osteoblasts and fewer sclerostin + osteocytes. CONCLUSIONS: The variation of tibial plateau STB remodeling activity and microstructure was associated with HKA angle and cartilage degradation. Knee malalignment may cause abnormal STB remodeling and microstructural sclerosis, which may potentially affect load stress transmission from the cartilage to the STB, thus resulting in accelerated knee OA progression.
Assuntos
Remodelação Óssea , Osso Esponjoso/patologia , Osteoartrite do Joelho/patologia , Idoso , Articulação do Tornozelo/diagnóstico por imagem , Cartilagem Articular , Estudos Transversais , Feminino , Articulação do Quadril/diagnóstico por imagem , Humanos , Articulação do Joelho/diagnóstico por imagem , Masculino , Pessoa de Meia-IdadeRESUMO
Macro- and microarchitectural, bone material property, dynamic histomorphometric, and bone turnover marker data were studied in normal bone mineral density (BMD) post-menopausal women with fragility fracture. Women with fracture had thinner iliac cortices and more homogeneous bone material properties in cortical bone than age/BMD-matched non-fracture women. Low cortical thickness and bone tissue heterogeneity in normal BMD women are associated with prevalent fragility fracture. INTRODUCTION: Bone mass (bone mineral density, (BMD)) of the spine and hip is today's best single measurement for evaluating future fragility fracture risk. However, the majority of fragility fractures occur in women with BMD T-score above the WHO osteoporotic BMD threshold of - 2.5, indicating that non-BMD endpoints may play a role in their fragility fractures. We hypothesize that in non-osteoporotic women, bone micoarchitecture, bone material properties, dynamic histomorphometric endpoints, and bone turnover markers are related to fragility fracture. METHODS: Two groups (N = 60 each) of post-menopausal women with total hip BMD T-score ranging from + 0.3 to -2.49 were recruited: fragility fracture and age/BMD-matched, non-fragility fracture women. Normal (T-score > - 0.99) and osteopenic (T-score ≤ - 1.0) BMD cohorts were designated within both the fracture and non-fracture groups. Transiliac biopsy specimens were obtained to evaluate dynamic histomorphometric and microarchitectural endpoints and bone material properties by static and dynamic nanoindentation testing. All variables for fracture and non-fracture women within each BMD cohort were compared by the Wilcoxon signed-rank test (P < 0.01). RESULTS: Compared to non-fracture/normal BMD women, fracture/normal BMD women display lower iliac cortical thickness (- 12%, P = 0.0041) and lower heterogeneity of hardness (- 27%, P = 0.0068), elastic modulus (- 35%, P = 0.0009), and storage modulus (- 23%, P = 0.0054) in the cortical bone tissue, and lower heterogeneity of hardness (- 13%, P = 0.0088) in the trabecular bone tissue. Osteopenic women had no abnormalities related to fracture status. CONCLUSION: Post-menopausal women with normal BMD and fragility fracture have low cortical thickness and heterogeneity of several bone material properties in cortical and trabecular mineralized bone tissue. These differences may explain a portion of the excess bone fragility in women with normal BMD and fragility fracture.
Assuntos
Fraturas Ósseas , Fraturas por Osteoporose , Densidade Óssea , Remodelação Óssea , Osso Esponjoso/patologia , Feminino , Humanos , Ílio , Fraturas por Osteoporose/etiologia , Fraturas por Osteoporose/patologia , Pós-MenopausaRESUMO
The impact of cryptogenic cirrhosis on skeleton has not been studied in Indian context. So this study investigated bone health in male patients with early cryptogenic cirrhosis as defined by Child-Turcot-Pugh A (CTP-A) categorization and compared it with patients diagnosed to have hepatitis B related chronic liver disease (CLD) on treatment and age, sex-matched healthy controls. It was a cross-sectional study, in which thirty male subjects were recruited in each group. Bone mineral density (BMD), trabecular bone score (TBS), hip structural analysis (HSA) and bone mineral parameters were assessed. The mean ±SD age of the study subjects was 39.3 ± 9.2 years. The mean 25-hydroxy vitamin D was significantly lower in subjects with cryptogenic cirrhosis as compared to controls (pâ¯=â¯0.001). Subjects with cryptogenic cirrhosis had significantly lower (1.297 ± 0.099) TBS as compared to hepatitis-B related CLD (1.350 ± 0.094) control subjects (1.351 ± 0.088) (pâ¯=â¯0.04). BMD at the hip and lumbar spine was also significantly lower in subjects with cryptogenic cirrhosis as compared to hepatitis-B related CLD and healthy age matched controls (p < 0.05). Most components of HSA were significantly affected in subjects with cryptogenic cirrhosis as compared to control subjects (p < 0.05). Patients with cryptogenic cirrhosis had significantly low TBS and BMD lumbar spine and hip as well as poor proximal hip geometry which may be good predictor of future fragility fractures.
Assuntos
Hepatite B , Fraturas por Osteoporose , Absorciometria de Fóton , Adulto , Densidade Óssea , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/patologia , Estudos Transversais , Hepatite B/patologia , Humanos , Cirrose Hepática/diagnóstico por imagem , Vértebras Lombares/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Minerais , Fraturas por Osteoporose/patologiaRESUMO
The damaging effects of ionizing radiation (IR) on bone mass are well-documented in mice and humans and are most likely due to increased osteoclast number and function. However, the mechanisms leading to inappropriate increases in osteoclastic bone resorption are only partially understood. Here, we show that exposure to multiple fractions of low-doses (10 fractions of 0.4 Gy total body irradiation [TBI]/week, i.e., fractionated exposure) and/or a single exposure to the same total dose of 4 Gy TBI causes a decrease in trabecular, but not cortical, bone mass in young adult male mice. This damaging effect was associated with highly activated bone resorption. Both osteoclast differentiation and maturation increased in cultures of bone marrow-derived macrophages from mice exposed to either fractionated or singular TBI. IR also increased the expression and enzymatic activity of mitochondrial deacetylase Sirtuin-3 (Sirt3)-an essential protein for osteoclast mitochondrial activity and bone resorption in the development of osteoporosis. Osteoclast progenitors lacking Sirt3 exposed to IR exhibited impaired resorptive activity. Taken together, targeting impairment of osteoclast mitochondrial activity could be a novel therapeutic strategy for IR-induced bone loss, and Sirt3 is likely a major mediator of this effect.
Assuntos
Reabsorção Óssea/patologia , Mitocôndrias/metabolismo , Mitocôndrias/efeitos da radiação , Osteoclastos/metabolismo , Osteoclastos/efeitos da radiação , Radiação Ionizante , Animais , Osso Esponjoso/patologia , Osso Esponjoso/efeitos da radiação , Respiração Celular/efeitos da radiação , Fracionamento da Dose de Radiação , Masculino , Camundongos Endogâmicos C57BL , Sirtuína 3/metabolismoRESUMO
Breast cancer, a common malignancy for women, preferentially metastasizes to bone and obesity elevates the chance of its progression. While mechanical loading can suppress obesity and tumor-driven osteolysis, its effect on bone-metastasized obese mice has not been investigated. Here, we hypothesized that mechanical loading can lessen obesity-associated bone degradation in tumor-invaded bone by regulating the fate of bone marrow-derived cells. In this study, the effects of mechanical loading in obese mice were evaluated through X-ray imaging, histology, cytology, and molecular analyses. Tumor inoculation to the tibia elevated body fat composition, osteolytic lesions, and tibia destruction, and these pathologic changes were stimulated by the high-fat diet (HFD). However, mechanical loading markedly reduced these changes. It suppressed osteoclastogenesis by downregulating receptor activator of nuclear factor Kappa-B ligand and cathepsin K and promoted osteogenesis, which was associated with the upregulation of OPG and downregulation of C/enhancer-binding protein alpha and proliferator-activated receptor gamma for adipogenic differentiation. Furthermore, it decreased the levels of tumorigenic genes such as Rac1, MMP9, and interleukin 1ß. In summary, this study demonstrates that although a HFD aggravates bone metastases associated with breast cancer, mechanical loading significantly protected tumor-invaded bone by regulating the fate of bone marrow-derived cells. The current study suggests that mechanical loading can provide a noninvasive, palliative option for alleviating breast cancer-associated bone metastasis, in particular for obese patients.
Assuntos
Medula Óssea/patologia , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Microambiente Celular , Adipócitos/patologia , Adipogenia , Tecido Adiposo , Animais , Peso Corporal , Osso Esponjoso/patologia , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Camundongos Endogâmicos BALB C , Camundongos Obesos , Osteoblastos/patologia , Osteoclastos/patologia , Osteogênese , Osteólise/complicações , Osteólise/patologia , Suporte de CargaRESUMO
Supraphysiological levels of the osteoblast-enriched mineralization regulator ectonucleotide pyrophosphatase or phosphodiesterase-1 (NPP1) is associated with type 2 diabetes mellitus. We determined the impact of osteoblast-specific Enpp1 ablation on skeletal structure and metabolic phenotype in mice. Female, but not male, 6-week-old mice lacking osteoblast NPP1 expression (osteoblast-specific knockout [KO]) exhibited increased femoral bone volume or total volume (17.50% vs. 11.67%; p < .01), and reduced trabecular spacing (0.187 vs. 0.157 mm; p < .01) compared with floxed (control) mice. Furthermore, an enhanced ability of isolated osteoblasts from the osteoblast-specific KO to calcify their matrix in vitro compared to fl/fl osteoblasts was observed (p < .05). Male osteoblast-specific KO and fl/fl mice showed comparable glucose and insulin tolerance despite increased levels of insulin-sensitizing under-carboxylated osteocalcin (195% increase; p < .05). However, following high-fat-diet challenge, osteoblast-specific KO mice showed impaired glucose and insulin tolerance compared with fl/fl mice. These data highlight a crucial local role for osteoblast NPP1 in skeletal development and a secondary metabolic impact that predominantly maintains insulin sensitivity.
Assuntos
Osso e Ossos/enzimologia , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina , Osteoblastos/enzimologia , Osteogênese , Diester Fosfórico Hidrolases/deficiência , Pirofosfatases/deficiência , Animais , Biomarcadores/sangue , Glicemia/metabolismo , Osso e Ossos/patologia , Osso Esponjoso/enzimologia , Osso Esponjoso/patologia , Células Cultivadas , Modelos Animais de Doenças , Feminino , Fêmur/enzimologia , Fêmur/patologia , Insulina/sangue , Masculino , Camundongos Knockout , Osteoblastos/patologia , Osteocalcina/sangue , Diester Fosfórico Hidrolases/genética , Pirofosfatases/genética , Fatores Sexuais , Crânio/enzimologia , Crânio/patologia , Tíbia/enzimologia , Tíbia/patologiaRESUMO
Overexpression of the nucleotide-binding leucine-rich repeat protein 3 (NLRP3) inflammasome in chronic auto-immune diseases leads to skeletal anomalies, with severe osteopenia due to the activation of osteoclasts. Reproducing this phenotype in Nlrp3 knock-in mice has provided insights into the role of NLRP3 in bone metabolism. We studied the role of NLRP3 in physiological bone development using a complete Nlrp3 knock-out mouse model. We found impaired skeletal development in Nlrp3-/- mice, resulting in a shorter stature than that of Nlrp3+/+ mice. These growth defects were associated with altered femur bone growth, characterized by a deficient growth plate and an osteopenic profile of the trabeculae. No differences in osteoclast recruitment or activity were observed. Instead, Nlrp3-/- femurs showed a less mineralized matrix in the trabeculae than those of Nlrp3+/+ mice, as well as less bone sialoprotein (BSP) expressing hypertrophic chondrocytes. In vitro, primary osteoblasts lacking NLRP3 expression showed defective mineralization, together with the downregulation of BSP expression. Finally, follow-up by micro-CT highlighted the role of NLPR3 in bone growth, occurring early in living mice, as the osteopenic phenotype diminishes over time. Overall, our data suggest that NLRP3 is involved in bone edification via the regulation of hypertrophic chondrocyte maturation and osteoblast activity. Furthermore, the defect appeared to be transitory, as the skeleton recovered with aging.
Assuntos
Osso Esponjoso/crescimento & desenvolvimento , Diferenciação Celular , Fêmur/crescimento & desenvolvimento , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Osteoblastos/metabolismo , Osteogênese , Fatores Etários , Animais , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/metabolismo , Osso Esponjoso/patologia , Células Cultivadas , Condrócitos/metabolismo , Condrócitos/patologia , Feminino , Fêmur/diagnóstico por imagem , Fêmur/metabolismo , Fêmur/patologia , Genótipo , Inflamassomos/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Osteoblastos/patologia , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteopontina/metabolismo , Fenótipo , Microtomografia por Raio-XRESUMO
Type 1 diabetes mellitus (T1DM) is characterized by hyperglycemia manifesting as insufficient insulin. Toll-like receptor-4 (TLR4) has been implicated in diabetic osteoporosis. We established streptozotocin (STZ)-induced diabetic mouse model and examined the relevant osteoporosis factors in different experimental groups, the WT-CON group, WT-STZ group, KO-CON group and KO-STZ group, respectively. No obvious protection of TLR4 deletion was shown in mice with diabetes. There was no obvious difference in the body weight or blood glucose concentration between WT-STZ group and KO-STZ group. However, TLR4 deletion reduced the receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation. Furthermore, TLR4 knockout attenuated STZ-induced diabetic osteoporosis via inhibiting osteoblasts and pre-inflammation factors mediated by the NF-κB pathway. TLR4 deletion ameliorated STZ-induced diabetic osteoporosis in mice, and TLR4 may be used as a potential therapeutic target for the treatment of diabetic osteoporosis.
Assuntos
Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Modelos Animais de Doenças , Osteoporose/induzido quimicamente , Osteoporose/genética , Estreptozocina , Receptor 4 Toll-Like/deficiência , Receptor 4 Toll-Like/genética , Animais , Osso Esponjoso/citologia , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/patologia , Diferenciação Celular/genética , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/genética , Masculino , Camundongos , Terapia de Alvo Molecular , Fator 88 de Diferenciação Mieloide/metabolismo , Osteoclastos/citologia , Osteoclastos/patologia , Osteoporose/complicações , Osteoporose/patologia , Ligante RANK/metabolismo , Tíbia/citologia , Tíbia/diagnóstico por imagem , Tíbia/patologia , Microtomografia por Raio-XRESUMO
OBJECTIVE: To delineate the activities of decorin and biglycan in the progression of post-traumatic osteoarthritis (PTOA). DESIGN: Three-month-old inducible biglycan (BgniKO) and decorin/biglycan compound (Dcn/BgniKO) knockout mice were subjected to the destabilization of the medial meniscus (DMM) surgery to induce PTOA. The OA phenotype was evaluated by assessing joint structure and sulfated glycosaminoglycan (sGAG) staining via histology, surface collagen fibril nanostructure and calcium content via scanning electron microscopy, tissue modulus via atomic force microscopy-nanoindentation, as well as subchondral bone structure and meniscus ossification via micro-computed tomography. Outcomes were compared with previous findings in the inducible decorin (DcniKO) knockout mice. RESULTS: In the DMM model, BgniKO mice developed similar degree of OA as the control (0.44 [-0.18 1.05] difference in modified Mankin score), different from the more severe OA phenotype observed in DcniKO mice (1.38 [0.91 1.85] difference). Dcn/BgniKO mice exhibited similar histological OA phenotype as DcniKO mice (1.51 [0.97 2.04] difference vs control), including aggravated loss of sGAGs, salient surface fibrillation and formation of osteophyte. Meanwhile, Dcn/BgniKO mice showed further cartilage thinning than DcniKO mice, resulting in the exposure of underlying calcified tissues and aberrantly high surface modulus. BgniKO and Dcn/BgniKO mice developed altered subchondral trabecular bone structure in both Sham and DMM groups, while DcniKO and control mice did not. CONCLUSION: In PTOA, decorin plays a more crucial role than biglycan in regulating cartilage degeneration, while biglycan is more important in regulating subchondral bone structure. The two have distinct activities and modest synergy in the pathogenesis of PTOA.
Assuntos
Biglicano/deficiência , Decorina/deficiência , Progressão da Doença , Osteoartrite/patologia , Animais , Biglicano/genética , Osso Esponjoso/patologia , Cartilagem Articular , Decorina/genética , Modelos Animais de Doenças , Meniscos Tibiais/patologia , Camundongos Knockout , Ossificação Heterotópica/patologia , Osteoartrite/genética , Osteófito/patologia , Lesões do Menisco Tibial/patologiaRESUMO
INTRODUCTION: There is a need for a cost-effective method to identify individuals with a high risk of osteoporosis. This study aimed to investigate the suitability of hand grip strength in predicting the risk of osteoporosis in Asian adults. MATERIALS AND METHODS: In this cross-sectional, hospital-based study of 1007 participants, the bone mineral density of the spine and hips was evaluated using dual-energy X-ray absorptiometry according to the 2019 International Society for Clinical Densitometry official positions. Bone microarchitecture was evaluated using the trabecular bone score, and hand grip strength was measured in the dominant hand using a hand digital dynamometer. RESULTS: Hand grip strength was significantly related to bone density and bone microarchitecture. Moreover, hand grip strength was a significant predictor of osteoporosis in both women and men. For osteoporosis prediction in women, a threshold of 21.9 kg of hand grip strength had a sensitivity of 59%, specificity of 59%, and area under the curve (AUC) of 0.61. In men, a threshold of 28.7 kg had a sensitivity of 66%, specificity of 78%, and AUC of 0.75. The optimal cutoff strengths for osteoporosis depended on age and sex. CONCLUSION: The measurement of hand grip strength is a simple, cost-effective and an easy assessment method for identifying individuals at a high risk of osteoporosis. The cutoff strength for evaluating osteoporosis in adults is age and sex specific.
Assuntos
Povo Asiático , Força da Mão/fisiologia , Osteoporose/diagnóstico , Osteoporose/fisiopatologia , Absorciometria de Fóton , Adulto , Idoso , Densidade Óssea , Osso Esponjoso/patologia , Osso Esponjoso/fisiopatologia , Estudos Transversais , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Osteoporose/diagnóstico por imagem , Fatores de RiscoRESUMO
Rhaponticin is a constituent isolated from numerous medicinal herbs. It has been reported earlier that rhaponticin possesses numerous biological effects like antiallergic, antidiabetic, hepatoprotective, and antithrombosis. The goal of this exploration was to scrutinize the therapeutic potential of rhaponticin on ovariectomy (OVX)-triggered osteoporosis in rats. Female Sprague Dawley rats were arbitrarily allocated to a sham-operated control group I, group II, which underwent OVX, and groups III and IV that underwent OVX were administered with rhaponticin (10 and 20 mg/kg). Rhaponticin was supplemented orally after 4 weeks of OVX and continued for about 16 weeks. Our findings exhibit that rhaponticin prevented the BMD diminution of femurs, induced by OVX, and protected the worsening of trabecular microarchitecture that are assisted through a noteworthy decline in skeletal remodeling as noticed through the diminished status of bone markers in a dose-dependent manner (10 and 20 mg/kg). OVX rats treated with rhaponticin efficiently enhanced body weight, lipid profiles, uterine index, bone turnover markers, inflammatory markers, and augmented the incidence of calcium in the OVX rats. Rhaponticin was established to restrain the functions of acid phosphatase, estradiol, and bone gla protein in OVX rats. Also, rhaponticin displayed some beneficial effects on histomorphometric and histopathological examination. It was observed that tabular area and thickness were reinstated in sham control and rhaponticin-treated OVX rats. We recognized that rhaponticin did not induce a damaging outcome on the skeletal organization of OVX rats. Moreover, we denote that rhaponticin can be an exceptional agent for the treatment and deal with associated bone diseases.
Assuntos
Densidade Óssea/efeitos dos fármacos , Osteoporose/prevenção & controle , Ovariectomia , Estilbenos/farmacologia , Animais , Osso Esponjoso/metabolismo , Osso Esponjoso/patologia , Feminino , Osteoporose/metabolismo , Osteoporose/patologia , Ratos , Ratos Sprague-DawleyRESUMO
INTRODUCTION: Thyrotropin stimulating hormone (TSH) suppression in patients with differentiated thyroid cancer (DTC) aims to decrease the growth and proliferation of thyroid cancer cells. However, the effect of TSH-suppressive therapy on bone microarchitecture remains undefined. METHODS: Cross-sectional study including 43 women with DTC undergoing TSH-suppressive therapy (sTSH) compared to 20 women also on levothyroxine (LT4) therapy but with TSH in the low-normal range (nTSH) since the thyroid surgery. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA), and trabecular bone score (TBS) was evaluated using the TBS iNsigth software. Fracture risk assessed by FRAX, with and without TBS, was calculated. The relationship between suppressive therapy-related parameters and bone parameters was investigated. RESULTS: The TBS mean values were not significantly different in the sTSH and nTSH groups (1.273 ± 0.12 vs 1.307 ± 0.14, p = 0.7197). In both groups, postmenopausal women had degraded microarchitecture (TBS 1.216 ± 0.11 vs 1.213 ± 0.09, p = 0.9333), while premenopausal women had normal microarchitecture (1.328 ± 0.11 vs 1.401 ± 0.12, p = 0.195). The percentage of all postmenopausal women with degraded TBS was 54.7%, while the percentage of osteoporosis diagnoses was 16.1%. The TBS-adjusted FRAX-probability of fracture was similar in sTSH and nTSH groups. Body mass index (BMI) and menopausal status were the only variables associated with TBS and BMD. CONCLUSION: Trabecular microarchitecture assessed by TBS was similar between women on long-term suppressive therapy in DTC and those on LT4 replacement therapy aiming at a TSH level within the low-normal reference range. Low TBS values were observed in postmenopausal women of both groups, suggesting that not only suppressed TSH levels but also a low-normal TSH is associated with deteriorated bone microarchitecture in postmenopausal women following total thyroidectomy.
Assuntos
Adenocarcinoma/tratamento farmacológico , Densidade Óssea , Osso Esponjoso/patologia , Osteoporose/patologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Tireotropina/antagonistas & inibidores , Tiroxina/efeitos adversos , Adenocarcinoma/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil/epidemiologia , Osso Esponjoso/efeitos dos fármacos , Estudos Transversais , Feminino , Seguimentos , Humanos , Menopausa , Pessoa de Meia-Idade , Osteoporose/induzido quimicamente , Osteoporose/epidemiologia , Prognóstico , Neoplasias da Glândula Tireoide/patologia , Adulto JovemRESUMO
The study investigated the effects of long-term glucocorticoid (GC) administration on bone remodelling, microstructure, and biomechanical strength in cortical and cancellous (trabecular) bones. Thirty-one female Sprague-Dawley rats were randomly divided into three dexamethasone (Dex) dosage groups, 1.0, 2.5, and 5.0 mg/kg twice a week for 8 weeks, and one control group treated with saline. At the end of the experiment, the tibia of one side and the fourth lumbar vertebrae were processed into sections for a histomorphometric analysis, while the femur of the same side and the fifth vertebrae were isolated for a biomechanical test. A dose-dependent decline in bone formation was observed in both trabecular and cortical (periosteal and endosteal) bones. In contrast, bone resorption was inhibited only in cancellous bone in the two higher dose groups and not dose-related. The ratio of Node/Termini increased, while marrow star volume (MSV) decreased in all Dex groups in metaphyseal trabecular bones, both of which were dose-dependent. Subendosteal cortex porosity increased in parallel with non-uniform trabecular distribution, but cortical thickness remained unchanged. Interestingly, there were no significant changes in microstructure or mechanical strength in lumbar trabecular bone. The cortical elastic load was dose-independently reduced in all three Dex groups when compared with the control group. In summary, bone remodelling was dose-dependently inhibited in cancellous bones but enhanced in intracortical bones. The non-uniform distribution of trabecular bone and increased porosity in the inner edge of cortical bone were both in parallel with GC dosage, and the porosity increase was more likely to occur, leading to reduced cortical mechanical strength.
Assuntos
Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Reabsorção Óssea/tratamento farmacológico , Osso Esponjoso/patologia , Osso Cortical/efeitos dos fármacos , Glucocorticoides/farmacologia , Animais , Reabsorção Óssea/patologia , Osso Esponjoso/efeitos dos fármacos , Feminino , Ratos , Ratos Sprague-DawleyRESUMO
Rheumatoid arthritis (RA) affects the hip joints. The microarchitecture of the cancellous bone in RA-affected hip joints has been unclear. Here we investigated the bone metabolism changes in the subcapital cancellous bone of destructive hips of RA patients (n=26 patients; 28 hip joints) which were classified by Larsen grade on X-ray into the groups: destructive hip (Des) (Larsen grade IV, n=18) and neck fracture (Fx) (Larsen grade 0 or 1, n=10). The femoral heads of the Des-group showed significantly higher trabecular thickness versus those of the Fx-group (179±30.8 vs. 151±23.5 µm, p=0.02). The Des-group had significantly higher osteoid volume/tissue volume (OV/TV) and osteoid volume/bone volume (OV/BV) ratios than the Fx-group (OV/TV: 0.72±0.70% vs. 0.27±0.32%, p=0.028; OV/BV: 2.96±2.85% vs. 1.24±1.31%, p=0.039). The osteoblast and osteoclast surface areas of the Des-group were remarkably higher than those of the Fx-group (9.80±10.9 vs. 0.15±0.15%, p=0.0005; 0.34±0.48 vs. 0.06±0.06%, p=0.0285, respectively). The T-scores of hip (femoral neck) bone mineral density (BMD) of the Fx-group were significantly lower versus those of the Des-group (-3.1±0.76 vs. -1.6±1.17, p<0.01). Increased osteoid and resorption parameters and higher femoral neck BMD demonstrate a high bone-turnover state in response to destructive changes in the hips of RA patients.