Irisin Protects against Loss of Trabecular Bone Mass and Strength in Adult Ovariectomized Mice by Stimulating Osteoblast Activity.

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.

Microstructural and cellular characterisation of the subchondral trabecular bone in human knee and hip osteoarthritis using synchrotron tomography.

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.

CCL12 induces trabecular bone loss by stimulating RANKL production in BMSCs during acute lung injury.

In the last three years, the capacity of health care systems and the public health policies of governments worldwide were challenged by the spread of SARS-CoV-2. Mortality due to SARS-CoV-2 mainly resulted from the development of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Moreover, millions of people who survived ALI/ARDS in SARS-CoV-2 infection suffer from multiple lung inflammation-induced complications that lead to disability and even death. The lung-bone axis refers to the relationship between lung inflammatory diseases (COPD, asthma, and cystic fibrosis) and bone diseases, including osteopenia/osteoporosis. Compared to chronic lung diseases, the influence of ALI on the skeleton has not been investigated until now. Therefore, we investigated the effect of ALI on bone phenotypes in mice to elucidate the underlying mechanisms. In vivo bone resorption enhancement and trabecular bone loss were observed in LPS-induced ALI mice. Moreover, chemokine (C-C motif) ligand 12 (CCL12) accumulated in the serum and bone marrow. In vivo global ablation of CCL12 or conditional ablation of CCR2 in bone marrow stromal cells (BMSCs) inhibited bone resorption and abrogated trabecular bone loss in ALI mice. Furthermore, we provided evidence that CCL12 promoted bone resorption by stimulating RANKL production in BMSCs, and the CCR2/Jak2/STAT4 axis played an essential role in this process. Our study provides information regarding the pathogenesis of ALI and lays the groundwork for future research to identify new targets to treat lung inflammation-induced bone loss.

Bone Marrow Adipose Tissue Is Increased in Postmenopausal Women With Postsurgical Hypoparathyroidism.

CONTEXT: Suppression of bone turnover, greater trabecular volume, and normal-high normal all-site bone mineral density (BMD) are hallmarks of postsurgical hypoparathyroidism (HypoPT). Impairment in the trabecular microarchitecture with possible higher risk of vertebral fractures (VF) in women with postmenopausal HypoPT has also been described. Currently, no data on bone marrow adipose tissue (BMAT) are available in HypoPT. OBJECTIVE: To assess BMAT by magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H-MRS) in postmenopausal women with chronic postsurgical HypoPT. METHODS: This cross-sectional pilot study, conducted at an ambulatory referral center, included 29 postmenopausal women (mean age 66 ± 8.4 years) with postsurgical HypoPT and 31 healthy postmenopausal women (mean age 63 ± 8.5). Lumbar spine MRI was performed and BMAT was measured by applying PRESS sequences on the L3 body. Lumbar spine, femoral neck, and total hip BMD were measured by dual x-ray absorptiometry (DXA); site-matched spine trabecular bone score (TBS) was calculated by TBS iNsight (Medimaps, Switzerland); VF assessment was performed with lateral thoracic and lumbar spine DXA. RESULTS: Fat content (FC) and saturation level (SL%) were higher (P <.0001 and P <.001), while water content (W) was lower in HypoPT compared to controls (P <.0001). FC significantly correlated with years since menopause and body weight (P <.05) in HypoPT, while TBS negatively correlated with FC and SL% (P <.05) and positively with residual lipids (RL) and W (P <.05). CONCLUSION: We demonstrate for the first time that BMAT is increased in postmenopausal women with postsurgical hypoparathyroidism and negatively associated with trabecular microarchitecture.

Trabecular bone score, bone marrow fat and vertebral fractures in cushing syndrome.

OBJECTIVE: Prediction of fragility fractures in Cushing syndrome (CS) is a challenge since dual energy X-ray absorptiometry (DXA) measurement of bone mineral density (BMD) does not capture all the alterations in bone microstructure induced by glucocorticoid excess. In this study we investigated the relationship between trabecular bone score (TBS), bone marrow fat (BMF) and vertebral fractures (VFs) in endogenous CS. DESIGN: Cross-sectional. METHODS: Thirty subjects (7 M and 23 F, mean age 44.8 ± 13.4 yrs, range: 25-71) with active hypercortisolism were evaluated for VFs by quantitative morphometry, BMD and TBS by lumbar spine DXA and BMF by single-voxel magnetic resonance spectroscopy of vertebral body of L3. RESULTS: Subjects with VFs (17 cases; 56.7%) had higher BMF (P = 0.014) and lower BMD T-score (P = 0.012) and TBS (P = 0.004) as compared to those without VFs. Prevalence of VFs resulted to be significantly higher in individuals with impaired TBS as compared to those with normal TBS (77.8% vs. 25.0%; P = 0.008). Among patients with VFs, only 6 (35.3%) had either osteoporosis or "low BMD for age". In logistic regression analysis, impaired TBS maintained the significant association with VFs [odds ratio (OR) 6.60, 95% C.I. 1.07-40.61; P = 0.042] independently of BMF (OR 1.03, 95% C.I. 0.99-1.08; P = 0.152). CONCLUSIONS: TBS might be more accurate than BMF in identifying subjects with active CS and skeletal fragility at risk of VFs. SIGNIFICANCE STATEMENT: Excess in glucocorticoids is associated with alterations in bone remodeling and metabolism, leading to fragility fractures regardless of bone mineral density, making more challenging for the clinician the identification of high-risk population and the definition of preventing strategies. In this context, instrumental parameters suggestive of bone quality alterations and predictive of increased fracture risk are needed. In this study, we found CS patients to have bone quality alterations as indicated by the decreased trabecular bone score and increased bone marrow fat, as measured by DEXA and MRI respectively. Both parameters were associated with high risk of VFs, and were inversely correlated, although TBS seems to be more accurate than BMF in fractures prediction in this clinical setting.

Simple curettage and allogeneic cancellous bone chip impaction grafting in solitary enchondroma of the short tubular bones of the hand.

Enchondroma is the most common bone tumor in the hand. While standard surgical procedure is intra-lesional excision and bone grafting, there is a dispute between allogeneic bone, autogenous bone, and synthetic bone substitute grafting. Diverse adjuvant treatments have been introduced to reduce recurrence, but results are mixed with controversies. Meanwhile, whether existing descriptive classification could predict treatment outcome remains unclear. Thus, we reviewed patients with solitary enchondroma of the hand who underwent simple curettage followed by allogeneic cancellous bone chip impaction grafting. Eighty-eight patients with more than 5 years of follow-up were enrolled. Demographic data, local recurrence, and complications were reviewed. Duration of consolidation and the difference according to Takigawa classification were assessed. Range of motion (ROM), and functional scores were also evaluated. There were 51 women and 37 men, with a mean age of 37.9 years. Mean follow-up was 10.2 years. Recurrence occurred only in one patient. There was no complication. Mean postoperative total active motions of fingers and thumb were 239° and 132.9°. Mean modified Disabilities of the Arm, Shoulder, Hand score, and Musculoskeletal Tumor Society Score were 1.63, and 99.2 at the last follow-up. Consolidation, ROM, and functional scores according to Takigawa classification showed no significant differences. This study suggests that simple curettage with impaction grafting of allogeneic cancellous bone chip is a feasible method for treating solitary enchondromas involving short tubular bone of the hand with good long-term outcomes. Postoperative recurrence and complication rates were very low. Radiographic and clinical results were good regardless of the previous radiological classification.

Investigating the subchondral trabecular bone microstructure in patients with osteonecrosis of the femoral head using multi-detector row computed tomography.

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.

Trabecular bone microcrack accumulation in patients treated with bisphosphonates for durations up to 16 years.

This study quantified the length, number, and density of microcracks in bone from patients treated with bisphosphonates as a function of duration. Anterior iliac crest bone samples from 51 osteoporotic Caucasian females continuously treated with oral bisphosphonates for 1-16 years were obtained by bone biopsy. Samples were histologically processed and analyzed for bone area, microcrack number, and microcrack length. The analyses used statistical modeling and considered patient age, bone mineral density, bone volume/total volume, trabecular thickness, and bone turnover as potential covariates. Microcrack density (number of microcracks/total examined bone area) was linearly related (p = 0.018) to bisphosphonate treatment duration. None of the analyzed covariates contributed significantly to the observed relationship between microcrack density and bisphosphonate treatment duration. Observed increases in microcrack density with increasing bisphosphonate treatment duration is important because increasing levels of microcracks may not only affect bone remodeling but also reduce elastic modulus and are suspected to adversely affect other mechanical properties that may influence fracture risk. The present findings add to our prior results showing changes in bone material properties and modulus with bisphosphonate treatment duration and thereby provide a more comprehensive assessment of the relationship between bisphosphonate treatment duration and bone quality. Statement of Clinical Significance: The present findings provide information guiding clinical use of oral bisphosphonates for post-menopausal osteoporosis therapy.

mRNA expression profiling of the cancellous bone in patients with idiopathic osteonecrosis of the femoral head by whole-transcriptome sequencing.

Idiopathic osteonecrosis of the femoral head (INFH) seriously affects patients' activities and is a heavy burden to society and patients' families. Therefore, the early diagnosis and treatment of INFH is essential in reducing pain and burden. In the present study, the cancellous bone under the cartilage of the femoral head was isolated from patients with INFH and femoral neck fracture (FNF). Histological examination revealed that the bone trabecular and the medullary cavity in the INFH group compared with those in the FNF group. Whole-transcriptome sequencing (WTS), a recently applied technology, plays a significant role in the screening of risk factors associated with the onset of femoral head necrosis. Herein, WTS was used to obtain the mRNA expression profile in the cancellous bone of the femoral head isolated from 5 patients with INFH and 5 patients with FNF. Compared with the FNF group, a total of 155 differentially expressed genes were identified in the INFH group. Among these genes, 96 and 59 were upregulated and downregulated, respectively. Reverse transcription-quantitative PCR and western blot analyses revealed that leucine-rich repeat-containing 17 (LRRC17) displayed the most significantly decreased mRNA and protein expression levels between the INFH and FNF groups. The expression profile of the differentially expressed genes and LRRC17 protein in the INFH and FNF groups was consistent with that obtained by WTS. LRRC17, a leucine repeat sequence, plays a significant role in regulating bone metabolism, thus indicating that LRRC17 downregulation could affect bone metabolism and could be considered a key factor in the pathogenesis of INFH.

Fibroma ossificante juvenil trabecular: relato de caso / Juvenile trabecular ossifying fibroma: case report / Fibroma osificante trabecular juvenil: reporte de un caso

O fibroma ossificante juvenil trabecular (FOJTr) é uma lesão fibro-óssea benigna rara de comportamento agressivo, alto potencial de recorrência, e acometimento no esqueleto craniofacial de crianças e adolescentes. Uma paciente do gênero feminino, 8 anos de idade, compareceu ao ambulatório de Patologia Oral e Maxilofacial da Universidade de Gurupi ­ UNIRG para avaliação clínica de um aumento de volume na região de corpo da mandíbula do lado esquerdo. Não havia sintomatologia dolorosa e sequer desconforto. Nos exames de imagem (radiografia panorâmica e tomografia computadorizada) foram observados uma extensa área radiolúcida que se estendia desde o primeiro molar permanente com rizogênese incompleta até o incisivo central do lado oposto. Após a realização da biópsia incisional e laudos histopatológicos realizou-se a remoção completa da lesão incluindo os remanescentes decíduos sobrejacentes ao fibroma. Nas imagens de controle pós-operatório aos 90 dias (radiografia panorâmica e tomografia computadorizada), notou-se sinais de neoformação óssea com espessamento basilar e os germes dos dentes permanentes em franco desenvolvimento. Diante disso, ressalta-se a importância do conhecimento dos aspectos clínicos, radiográficos e histopatológicos para a realização de um correto diagnóstico e tratamento adequado afim de reduzir as altas taxas de recidivas... (AU)

Trabecular juvenile ossifying fibroma (TrJOF) is a rare benign fibro-osseous lesion, with aggressive behavior, high recurrence potential, which affects the craniofacial skeleton of children and adolescents. This paper aims to describe a clinical case in a female patient, 8 years old, who attended the Oral and Maxillofacial Pathology outpatient clinic ­ Faculty of Dentistry ­ University of Gurupi - UNIRG, city of Gurupi - TOCANTINS - BRAZIL for clinical evaluation of an increased in volume in the region of the mandible body, on the left side. There was no painful symptomatology or even discomfort. Imaging examinations (panoramic radiography and computed tomography (CT) showed an extensive radiolucent area that extended from the first permanent molar with incomplete root formation to the central incisor on the opposite side. After performing an incisional biopsy and histopathological examination, the lesion was completely removed included the remainder deciduous teeth overlying the tumor. In the postoperative control images at 90 days (panoramic radiography and CT), signs of bone neoformation with basilar thickening and the germs of the permanent teeth in full development were noted. In view, this importance of knowledge of clinical, radiographic and histopathological aspects is emphasized for the realization of a correct diagnosis and adequate treatment in order to reduce the high rates of relapses... (AU)

El fibroma osificante trabecular juvenil (TRFOJ) es una lesión fibroósea benigna rara con comportamiento agresivo, alto potencial de recurrencia y afectación del esqueleto craneofacial de niños y adolescentes. Paciente femenina de 8 años de edad que acude al ambulatorio de Patología Oral y Maxilofacial de la Universidad de Gurupi - UNIRG para evaluación clínica de aumento de volumen en la región del cuerpo mandibular del lado izquierdo. No presentaba sintomatología dolorosa ni molestias. Los exámenes de imagen (radiografía panorámica y tomografía computarizada) mostraron una extensa área radiolúcida que se extendía desde el primer molar permanente con formación radicular incompleta hasta el incisivo central del lado opuesto. Tras realizar la biopsia incisional y los informes histopatológicos, se procedió a la extirpación total de la lesión, incluidos los remanentes caducos que recubrían el fibroma. En las imágenes de control postoperatorio a los 90 días (radiografía panorámica y tomografía computarizada), se observaron signos de neoformación ósea con engrosamiento basilar y los gérmenes de los dientes permanentes en pleno desarrollo. Por tanto, es importante conocer los aspectos clínicos, radiográficos e histopatológicos para la realización de un diagnóstico correcto y un tratamiento adecuado con el fin de reducir las altas tasas de recaídas... (AU)

Effect of Acetazolamide and Zoledronate on Simulated High Altitude-Induced Bone Loss.

Exposure to hypobaric hypoxia at high altitude puts mountaineers at risk of acute mountain sickness. The carbonic anhydrase inhibitor acetazolamide is used to accelerate acclimatization, when it is not feasible to make a controlled and slow ascend. Studies in rodents have suggested that exposure to hypobaric hypoxia deteriorates bone integrity and reduces bone strength. The study investigated the effect of treatment with acetazolamide and the bisphosphonate, zoledronate, on the skeletal effects of exposure to hypobaric hypoxia. Eighty 16-week-old female RjOrl : SWISS mice were divided into five groups: 1. Baseline; 2. Normobaric; 3. Hypobaric hypoxia; 4. Hypobaric hypoxia + acetazolamide, and 5. Hypobaric hypoxia + zoledronate. Acetazolamide was administered in the drinking water (62 mg/kg/day) for four weeks, and zoledronate (100 µg/kg) was administered as a single subcutaneous injection at study start. Exposure to hypobaric hypoxia significantly increased lung wet weight and decreased femoral cortical thickness. Trabecular bone was spared from the detrimental effects of hypobaric hypoxia, although a trend towards reduced bone volume fraction was found at the L4 vertebral body. Treatment with acetazolamide did not have any negative skeletal effects, but could not mitigate the altitude-induced bone loss. Zoledronate was able to prevent the altitude-induced reduction in cortical thickness. In conclusion, simulated high altitude affected primarily cortical bone, whereas trabecular bone was spared. Only treatment with zoledronate prevented the altitude-induced cortical bone loss. The study provides preclinical support for future studies of zoledronate as a potential pharmacological countermeasure for altitude-related bone loss.

Ionizing Radiation Activates Mitochondrial Function in Osteoclasts and Causes Bone Loss in Young Adult Male Mice.

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.

Bone architecture, bone material properties, and bone turnover in non-osteoporotic post-menopausal women with fragility fracture.

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.

Histone H3K27 demethylase, Utx, regulates osteoblast-to-osteocyte differentiation.

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.

Abnormal subchondral trabecular bone remodeling in knee osteoarthritis under the influence of knee alignment.

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.

Proximal Hip Geometry, Trabecular Bone Score, Bone Mineral Density and Bone Mineral Parameters in Patients With Cryptogenic and Hepatitis B Related Cirrhosis- A Study From the Indian Subcontinent.

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 (p = 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) (p = 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.

Fibroblast Growth Factor 23 and Klotho Are Associated With Trabecular Bone Score but Not Bone Mineral Density in the Early Stages of Chronic Kidney Disease: Results of the Cross-Sectional Study.

This study evaluates bone mineral density (BMD) and trabecular bone score (TBS) in relationship with new markers of chronic kidney disease (CKD), fibroblast growth factor 23 (FGF23), and klotho. The patients in this cross-sectional study were divided as follows: group A -patients in stages G1-3; group B -patients in stages G4 - 5 according to KDIGO. Plasma levels of soluble klotho and FGF23 were determined by ELISA. Bone mineral density (BMD) and trabecular bone score (TBS) were measured. 74 patients with CKD (mean age 68.8 years) were included in the study. Higher levels of FGF23 were observed in group B (N=15) compared to group A (N=59; p=0.001) were observed. FGF23 was higher in group A compared to group B. Significant difference in TBS within the first 3 stages of CKD was observed (mean TBS in G1=1.375 vs. G2=1.340 vs. G3a=1.24; p<0.05) and negative correlation of FGF23 and TBS (R=-0.33; p=0.05) and positive correlation between klotho and TBS (R=0.419; p=0.04) was observed. This study confirmed that FGF23 and klotho are associated with TBS, but TBS reflects a decrease in kidney function only in the first 3 stages of CKD. Thus, FGF23 and klotho together with TBS are promising markers of early trabecular bone impairment in CKD.

Prediction of Vertebral Fractures by Trabecular Bone Score in Patients With Ankylosing Spondylitis.

Ankylosing spondylarthritis (AS) is associated falsely increased lumbar spine bone mineral density (BMD). New tool for discrimination of subjects at fracture risk is needed. Vertebral fracture (VF) prediction of routine methods for osteoporosis assessment, BMD and trabecular bone score (TBS), in patients with AS. Cross-sectional study of all AS patients regularly followed at the rheumatology outpatient clinics of two centers. All subjects undergone BMD measurement at lumbar spine (LS), total hip (TH) and femoral neck (FN) using Hologic® Horizon device. TBS at L1-4 in all subjects by TBS InSight® software were assessed. Vertebral fracture assessment (VFA) was performed using the lateral spine imaging IVA™ and graded using Genant semi-quantitative approach. 119 AS subjects (90 males/29 females), mean age 47.6 years were included in the study. In 20 patients 34 VFs were detected, from whom 7 patients had multiple fractures. Subjects with VF were older and had lower FN BMD, TBS in comparison to non-VF subjects. No differences in LS BMD, FN BMD or BASDAI between groups were observed. Among patients with VF only 3 had T-score less than -2.5 but 7 has TBS less than 1.23 which means highly degraded microarchitecture. AS patients with VF have lower TBS and FN BMD in comparison to non-VF subjects. In addition, TBS was able to detect 20 % more VFs than BMD. Therefore, TBS seems promising in VF discrimination among patients with AS.

Osteoblast-specific inactivation of p53 results in locally increased bone formation.

Inactivation of the tumor suppressor p53 (encoded by the Trp53 gene) is relevant for development and growth of different cancers, including osteosarcoma, a primary bone tumor mostly affecting children and young adolescents. We have previously shown that deficiency of the ribosomal S6 kinase 2 (Rsk2) limits osteosarcoma growth in a transgenic mouse model overexpressing the proto-oncogene c-Fos. Our initial aim for the present study was to address the question, if Rsk2 deficiency would also influence osteosarcoma growth in another mouse model. For that purpose, we took advantage of Trp53fl/fl mice, which were crossed with Runx2Cre transgenic mice in order to inactivate p53 specifically in osteoblast lineage cells. However, since we unexpectedly identified Runx2Cre-mediated recombination also in the thymus, the majority of 6-month-old Trp53fl/fl;Runx2-Cre (thereafter termed Trp53Cre) animals displayed thymic lymphomas, similar to what has been described for Trp53-deficient mice. Since we did not detect osteosarcoma formation at that age, we could not follow our initial aim, but we studied the skeletal phenotype of Trp53Cre mice, with or without additional Rsk2 deficiency. Here we unexpectedly observed that Trp53Cre mice display a unique accumulation of trabecular bone in the midshaft region of the femur and the humerus, consistent with its previously established role as a negative regulator of osteoblastogenesis. Since this local bone mass increase in Trp53Cre mice was significantly reduced by Rsk2 deficiency, we isolated bone marrow cells from the different groups of mice and analyzed their behavior ex vivo. Here we observed a remarkable increase of colony formation, osteogenic differentiation and proliferation in Trp53Cre cultures, which was unaffected by Rsk2 deficiency. Our data thereby confirm a critical and tumorigenesis-independent function of p53 as a key regulator of mesenchymal cell differentiation.

Assessment of bone quality with trabecular bone score in patients with inflammatory bowel disease.

Inflammatory bowel disease (IBD) patients have a significant risk of developing bone loss. The trabecular bone score (TBS) is a relatively new parameter used to provide information on bone quality. The study cohort included 81 patients with IBD and 81 healthy controls. Blood tests, dual-energy x-ray absorptiometry (DXA), including TBS, were assessed. Harvey-Bradshaw Index (HBI) for Crohn's disease (CD) and the Partial Mayo Score for ulcerative colitis (UC) were used for evaluation of clinical disease activity. Compared with the healthy controls, the IBD patients had lower lumbar spine (LS) bone mineral density (BMD) (1.06 ± 0.18 vs. 1.16 ± 0.15 g/cm2, p < 0.005), hip BMD (0.88 ± 0.13 vs. 0.97 ± 0.13 g/cm2, p < 0.005) and TBS (1.38 ± 0.1 vs. 1.43 ± 0.1, p < 0.005) values. The patients with stricturing CD had lower TBS (1.32 ± 0.13 vs. 1.40 ± 0.9, p = 0.03) and LS BMD (0.92 ± 0.19 vs. 1.07 ± 0.1, p = 0.01) values compared with those with non-stricturing CD. Multivariate regression model analysis identified HBI as independent factor associated with TBS. Our results support that all DXA parameters are lower in patients with IBD than in healthy patients. Moreover, TBS is a valuable tool for assessment of bone impairment in active CD.