T. Stauber, Lena Wartosch, Svenja Vishnolia, A. Schulz, U. Kornak
After the discovery of abundant v-ATPase complexes in the osteoclast ruffled membrane it was obvious that in parallel a negative counter-ion needs to be transported across this membrane to allow for efficient transport of protons into the resorption lacuna. While different candidate proteins were discussed the osteopetrosis phenotype of Clcn7 knockout mice suggested that the chloride/proton-exchanger ClC-7 might be responsible for transporting the negative charge. In the following, individuals with autosomal recessive osteopetrosis (ARO) were found to carry biallelic CLCN7 pathogenic variants. Shortly thereafter, heterozygous pathogenic variants were identified as the exclusive cause of autosomal dominant osteopetrosis type 2 (ADO2). Since in most cell types other than osteoclasts ClC-7 resides in late endosomes and lysosomes, it took some time until the electrophysiological properties of ClC-7 were elucidated. Whereas most missense variants lead to reduced chloride currents, several variants with accelerated kinetics have been identified. Evidence for folding problems is also known for several missense variants. Paradoxically, a heterozygous activating variant in ClC-7 was described to cause lysosomal alteration, pigmentation defects, and intellectual disability without osteopetrosis. The counter-intuitive 2 Cl-/H+ exchange function of ClC-7 was shown to be physiologically important for intravesicular ion homeostasis. The lysosomal function of ClC-7 is also the reason why individuals with CLCN7-ARO can develop a storage disorder and neurodegeneration, a feature that is variable and difficult to predict. Furthermore, the low penetrance of heterozygous pathogenic CLCN7 variants and the clinical variability of ADO2 are incompletely understood. We aim to give an overview not only of the current knowledge about ClC-7 and its related pathologies, but also of the scientists and clinicians that paved the way for these discoveries.
{"title":"CLCN7, a gene shared by autosomal recessive and autosomal dominant osteopetrosis.","authors":"T. Stauber, Lena Wartosch, Svenja Vishnolia, A. Schulz, U. Kornak","doi":"10.2139/ssrn.4207532","DOIUrl":"https://doi.org/10.2139/ssrn.4207532","url":null,"abstract":"After the discovery of abundant v-ATPase complexes in the osteoclast ruffled membrane it was obvious that in parallel a negative counter-ion needs to be transported across this membrane to allow for efficient transport of protons into the resorption lacuna. While different candidate proteins were discussed the osteopetrosis phenotype of Clcn7 knockout mice suggested that the chloride/proton-exchanger ClC-7 might be responsible for transporting the negative charge. In the following, individuals with autosomal recessive osteopetrosis (ARO) were found to carry biallelic CLCN7 pathogenic variants. Shortly thereafter, heterozygous pathogenic variants were identified as the exclusive cause of autosomal dominant osteopetrosis type 2 (ADO2). Since in most cell types other than osteoclasts ClC-7 resides in late endosomes and lysosomes, it took some time until the electrophysiological properties of ClC-7 were elucidated. Whereas most missense variants lead to reduced chloride currents, several variants with accelerated kinetics have been identified. Evidence for folding problems is also known for several missense variants. Paradoxically, a heterozygous activating variant in ClC-7 was described to cause lysosomal alteration, pigmentation defects, and intellectual disability without osteopetrosis. The counter-intuitive 2 Cl-/H+ exchange function of ClC-7 was shown to be physiologically important for intravesicular ion homeostasis. The lysosomal function of ClC-7 is also the reason why individuals with CLCN7-ARO can develop a storage disorder and neurodegeneration, a feature that is variable and difficult to predict. Furthermore, the low penetrance of heterozygous pathogenic CLCN7 variants and the clinical variability of ADO2 are incompletely understood. We aim to give an overview not only of the current knowledge about ClC-7 and its related pathologies, but also of the scientists and clinicians that paved the way for these discoveries.","PeriodicalId":93913,"journal":{"name":"Bone","volume":"1 1","pages":"116639"},"PeriodicalIF":0.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42002337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matthias Walle, Dominic Eggemann, P. Atkins, Jack J. Kendall, K. Stock, Ralph Müller, C. Collins
Image quality degradation due to subject motion confounds the precision and reproducibility of measurements of bone density, morphology and mechanical properties from high-resolution peripheral quantitative computed tomography (HR-pQCT). Time-consuming operator-based scoring of motion artefacts remains the gold standard to determine the degree of acceptable motion. However, due to the subjectiveness of manual grading, HR-pQCT scans of poor quality, which cannot be used for analysis, may be accepted upon initial review, leaving patients with incomplete or inaccurate imaging results. Convolutional Neural Networks (CNNs) enable fast image analysis with relatively few pre-processing requirements in an operator-independent and fully automated way for image classification tasks. This study aimed to develop a CNN that can predict motion scores from HR-pQCT images, while also being aware of uncertain predictions that require manual confirmation. The CNN calculated motion scores within seconds and achieved a high F1-score (86.8 ± 2.8 %), with good precision (87.5 ± 2.7 %), recall (86.7 ± 2.9 %) and a substantial agreement with the ground truth measured by Cohen's kappa (κ = 68.6 ± 6.2 %); motion scores of the test dataset were predicted by the algorithm with comparable accuracy, precision, sensitivity and agreement as by the operators (p > 0.05). This post-processing approach may be used to assess the effect of motion scores on microstructural analysis and can be immediately implemented into clinical protocols, significantly reducing the time for quality assessment and control of HR-pQCT scans.
{"title":"Motion grading of high-resolution quantitative computed tomography supported by deep convolutional neural networks.","authors":"Matthias Walle, Dominic Eggemann, P. Atkins, Jack J. Kendall, K. Stock, Ralph Müller, C. Collins","doi":"10.2139/ssrn.4130780","DOIUrl":"https://doi.org/10.2139/ssrn.4130780","url":null,"abstract":"Image quality degradation due to subject motion confounds the precision and reproducibility of measurements of bone density, morphology and mechanical properties from high-resolution peripheral quantitative computed tomography (HR-pQCT). Time-consuming operator-based scoring of motion artefacts remains the gold standard to determine the degree of acceptable motion. However, due to the subjectiveness of manual grading, HR-pQCT scans of poor quality, which cannot be used for analysis, may be accepted upon initial review, leaving patients with incomplete or inaccurate imaging results. Convolutional Neural Networks (CNNs) enable fast image analysis with relatively few pre-processing requirements in an operator-independent and fully automated way for image classification tasks. This study aimed to develop a CNN that can predict motion scores from HR-pQCT images, while also being aware of uncertain predictions that require manual confirmation. The CNN calculated motion scores within seconds and achieved a high F1-score (86.8 ± 2.8 %), with good precision (87.5 ± 2.7 %), recall (86.7 ± 2.9 %) and a substantial agreement with the ground truth measured by Cohen's kappa (κ = 68.6 ± 6.2 %); motion scores of the test dataset were predicted by the algorithm with comparable accuracy, precision, sensitivity and agreement as by the operators (p > 0.05). This post-processing approach may be used to assess the effect of motion scores on microstructural analysis and can be immediately implemented into clinical protocols, significantly reducing the time for quality assessment and control of HR-pQCT scans.","PeriodicalId":93913,"journal":{"name":"Bone","volume":"1 1","pages":"116607"},"PeriodicalIF":0.0,"publicationDate":"2022-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49382975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yuri Seki, H. Takebe, T. Mizoguchi, Hiroaki Nakamura, M. Iijima, K. Irie, A. Hosoya
Orthodontic tooth movement (OTM) induces bone formation on the alveolar bone of the tension side; however, the mechanism of osteoblast differentiation is not fully understood. Gli1 is an essential transcription factor for hedgehog signaling and functions in undifferentiated cells during embryogenesis. In this study, we examined the differentiation of Gli1+ cells in the periodontal ligament (PDL) during OTM using a lineage-tracing analysis. After the final administration of tamoxifen for 2 days to 8-week-old Gli1-CreERT2/ROSA26-loxP-stop-loxP-tdTomato (iGli1/Tomato) mice, Gli1/Tomato+ cells were rarely observed near endomucin+ blood vessels in the PDL. Osteoblasts lining the alveolar bone did not exhibit Gli1/Tomato fluorescence. To move the first molar of iGli1/Tomato mice medially, nickel-titanium closed-coil springs were attached between the upper anterior alveolar bone and the first molar. Two days after OTM initiation, the number of Gli1/Tomato+ cells increased along with numerous PCNA+ cells in the PDL of the tension side. As some Gli1/Tomato+ cells exhibited positive expression of osterix, an osteoblast differentiation marker, Gli1+ cells probably differentiated into osteoblast progenitor cells. On day 10, the newly formed bone labeled by calcein administration during OTM was detected on the surface of the original alveolar bone of the tension side. Gli1/Tomato+ cells expressing osterix localized to the surface of the newly formed bone. In contrast, in the PDL of the compression side, Gli1/Tomato+ cells proliferated before day 10 and expressed type I collagen, suggesting that the Gli1+ cells also differentiated into fibroblasts. Collectively, these results demonstrate that Gli1+ cells in the PDL can differentiate into osteoblasts at the tension side and may function in bone remodeling as well as fibril formation in the PDL during OTM.
{"title":"Differentiation ability of Gli1+ cells during orthodontic tooth movement.","authors":"Yuri Seki, H. Takebe, T. Mizoguchi, Hiroaki Nakamura, M. Iijima, K. Irie, A. Hosoya","doi":"10.2139/ssrn.4214482","DOIUrl":"https://doi.org/10.2139/ssrn.4214482","url":null,"abstract":"Orthodontic tooth movement (OTM) induces bone formation on the alveolar bone of the tension side; however, the mechanism of osteoblast differentiation is not fully understood. Gli1 is an essential transcription factor for hedgehog signaling and functions in undifferentiated cells during embryogenesis. In this study, we examined the differentiation of Gli1+ cells in the periodontal ligament (PDL) during OTM using a lineage-tracing analysis. After the final administration of tamoxifen for 2 days to 8-week-old Gli1-CreERT2/ROSA26-loxP-stop-loxP-tdTomato (iGli1/Tomato) mice, Gli1/Tomato+ cells were rarely observed near endomucin+ blood vessels in the PDL. Osteoblasts lining the alveolar bone did not exhibit Gli1/Tomato fluorescence. To move the first molar of iGli1/Tomato mice medially, nickel-titanium closed-coil springs were attached between the upper anterior alveolar bone and the first molar. Two days after OTM initiation, the number of Gli1/Tomato+ cells increased along with numerous PCNA+ cells in the PDL of the tension side. As some Gli1/Tomato+ cells exhibited positive expression of osterix, an osteoblast differentiation marker, Gli1+ cells probably differentiated into osteoblast progenitor cells. On day 10, the newly formed bone labeled by calcein administration during OTM was detected on the surface of the original alveolar bone of the tension side. Gli1/Tomato+ cells expressing osterix localized to the surface of the newly formed bone. In contrast, in the PDL of the compression side, Gli1/Tomato+ cells proliferated before day 10 and expressed type I collagen, suggesting that the Gli1+ cells also differentiated into fibroblasts. Collectively, these results demonstrate that Gli1+ cells in the PDL can differentiate into osteoblasts at the tension side and may function in bone remodeling as well as fibril formation in the PDL during OTM.","PeriodicalId":93913,"journal":{"name":"Bone","volume":"1 1","pages":"116609"},"PeriodicalIF":0.0,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45723494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Esposito, M. Klüppel, Brittany M. Wilson, S. K. Meka, A. Spagnoli
Non-union fractures have considerable clinical and economic burdens and yet the underlying pathogenesis remains largely undetermined. The fracture healing process involves cellular differentiation, callus formation and remodeling, and implies the recruitment and differentiation of mesenchymal stem cells that are not fully characterized. C-X-C chemokine receptor 4 (CXCR4) and Insulin-like growth factor 1 receptor (IGF-1R) are expressed in the fracture callus, but their interactions still remain elusive. We hypothesized that the regulation of CXCR4 by IGF-1R signaling is essential to maintain the bone homeostasis and to promote fracture repair. By using a combination of in vivo and in vitro approaches, we found that conditional ablation of IGF-1R in osteochondroprogenitors led to defects in bone formation and mineralization that associated with altered expression of CXCR4 by a discrete population of endosteal cells. These defects were corrected by AMD3100 (a CXCR4 antagonist). Furthermore, we found that the inducible ablation of IGF-1R in osteochondroprogenitors led to fracture healing failure, that associated with an altered expression of CXCR4. In vivo AMD3100 treatment restored fracture healing and normalized CXCR4 expression. Moreover, we determined that these effects were mediated through the IGF-1R/Insulin receptor substrate 1 (IRS-1) signaling pathway. Taken together, our studies identified a novel population of endosteal cells that is functionally regulated through the modulation of CXCR4 by IGF-1R signaling, and such control is essential in bone homeostasis and fracture healing. Knowledge gained from these studies has the potential to accelerate the development of novel therapeutic interventions by targeting CXCR4 signaling to treat non-unions.
{"title":"CXCR4 mediates the effects of IGF-1R signaling in rodent bone homeostasis and fracture repair.","authors":"A. Esposito, M. Klüppel, Brittany M. Wilson, S. K. Meka, A. Spagnoli","doi":"10.2139/ssrn.4239423","DOIUrl":"https://doi.org/10.2139/ssrn.4239423","url":null,"abstract":"Non-union fractures have considerable clinical and economic burdens and yet the underlying pathogenesis remains largely undetermined. The fracture healing process involves cellular differentiation, callus formation and remodeling, and implies the recruitment and differentiation of mesenchymal stem cells that are not fully characterized. C-X-C chemokine receptor 4 (CXCR4) and Insulin-like growth factor 1 receptor (IGF-1R) are expressed in the fracture callus, but their interactions still remain elusive. We hypothesized that the regulation of CXCR4 by IGF-1R signaling is essential to maintain the bone homeostasis and to promote fracture repair. By using a combination of in vivo and in vitro approaches, we found that conditional ablation of IGF-1R in osteochondroprogenitors led to defects in bone formation and mineralization that associated with altered expression of CXCR4 by a discrete population of endosteal cells. These defects were corrected by AMD3100 (a CXCR4 antagonist). Furthermore, we found that the inducible ablation of IGF-1R in osteochondroprogenitors led to fracture healing failure, that associated with an altered expression of CXCR4. In vivo AMD3100 treatment restored fracture healing and normalized CXCR4 expression. Moreover, we determined that these effects were mediated through the IGF-1R/Insulin receptor substrate 1 (IRS-1) signaling pathway. Taken together, our studies identified a novel population of endosteal cells that is functionally regulated through the modulation of CXCR4 by IGF-1R signaling, and such control is essential in bone homeostasis and fracture healing. Knowledge gained from these studies has the potential to accelerate the development of novel therapeutic interventions by targeting CXCR4 signaling to treat non-unions.","PeriodicalId":93913,"journal":{"name":"Bone","volume":"1 1","pages":"116600"},"PeriodicalIF":0.0,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41937622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
V. De Martino, J. Pepe, Federica Biamonte, L. Colangelo, Laura Di Giuseppe, L. Nieddu, M. Occhiuto, S. Minisola, C. Cipriani
Neuromuscular impairment is described among the non-classical complications of primary hyperparathyroidism (PHPT). However, the extent of this complications and related mechanisms have not been fully addressed. The study aimed at assessing muscle strength and its main determinants in postmenopausal women with PHPT. We studied 48 postmenopausal women with PHPT (mean age 60.8 ± 5.6 SD years; BMI 25.6 ± 5.5 kg/m2) and 38 healthy postmenopausal women (mean age 58.6 ± 5.9; BMI 25.2 ± 3.5). In all subjects, the maximum voluntary contraction (MVC, Newton, N) was measured by Hand held Dynamometer (Kayser Italia srl, Livorno, Italy) and the lumbar spine, total hip, femoral neck, and non dominant distal one-third radius areal BMD (aBMD) by dual X-ray absorptiometry (DXA) (Hologic, Waltham, MA). Serum ionized calcium (Ca++), parathyroid hormone (PTH), phosphorus (P), and 25-hydroxyvitaminD [25 (OH)D] levels were measured in both groups. A subgroup of 30 PHPT women agreed to participate to the follow-up sub-study and were re-assessed 24 months after parathyroidectomy (n = 15) or after baseline evaluation (n = 15). Patients with PHPT had significant lower MVC values compared to healthy women (p < 0.001). As expected, serum Ca++ and PTH levels were higher and P lower in PHPT compared to controls. We observed a significant association between MVC and total hip and one-third radius aBMD (R = 0.320 and 0.370, p < 0.05) and negative association with Ca++ (R = -0.340, p < 0.05) in the PHPT group; MVC was positively associated with one-third radius aBMD (R = 0.360, p < 0.05) and negatively with age, BMI and myostatin (R = -0.390, -0.340 and -0.450, p < 0.05) in the group of healthy women. The linear model using BMI, Ca++, P, 25 (OH) D, PTH, myostatin, and aBMD as covariates showed that one-third radius aBMD was positively associated with MVC in PHPT patients (p < 0.02) and in healthy subjects (p < 0.001). Additionally, serum PTH and myostatin were negatively associated with MVC in healthy subjects (p < 0.03 and p < 0.01). The linear model showed that surgery was associated with an increase in MVC (p < 0.05) in PHPT patients after 24 months, all other variables being equal and by controlling for baseline values of MVC. Handgrip strength is significantly impaired in postmenopausal women with PHPT. Some common mechanisms influencing muscle function exist in PHPT and in healthy subjects; they are associated with the reduced aBMD at cortical sites. Hypercalcemia seems to be one of the main determinants of impairment in muscle strength in PHPT, while no role is played by myostatin.
{"title":"Impairment in muscle strength and its determinants in primary hyperparathyroidism: A study in postmenopausal women.","authors":"V. De Martino, J. Pepe, Federica Biamonte, L. Colangelo, Laura Di Giuseppe, L. Nieddu, M. Occhiuto, S. Minisola, C. Cipriani","doi":"10.2139/ssrn.4212322","DOIUrl":"https://doi.org/10.2139/ssrn.4212322","url":null,"abstract":"Neuromuscular impairment is described among the non-classical complications of primary hyperparathyroidism (PHPT). However, the extent of this complications and related mechanisms have not been fully addressed. The study aimed at assessing muscle strength and its main determinants in postmenopausal women with PHPT. We studied 48 postmenopausal women with PHPT (mean age 60.8 ± 5.6 SD years; BMI 25.6 ± 5.5 kg/m2) and 38 healthy postmenopausal women (mean age 58.6 ± 5.9; BMI 25.2 ± 3.5). In all subjects, the maximum voluntary contraction (MVC, Newton, N) was measured by Hand held Dynamometer (Kayser Italia srl, Livorno, Italy) and the lumbar spine, total hip, femoral neck, and non dominant distal one-third radius areal BMD (aBMD) by dual X-ray absorptiometry (DXA) (Hologic, Waltham, MA). Serum ionized calcium (Ca++), parathyroid hormone (PTH), phosphorus (P), and 25-hydroxyvitaminD [25 (OH)D] levels were measured in both groups. A subgroup of 30 PHPT women agreed to participate to the follow-up sub-study and were re-assessed 24 months after parathyroidectomy (n = 15) or after baseline evaluation (n = 15). Patients with PHPT had significant lower MVC values compared to healthy women (p < 0.001). As expected, serum Ca++ and PTH levels were higher and P lower in PHPT compared to controls. We observed a significant association between MVC and total hip and one-third radius aBMD (R = 0.320 and 0.370, p < 0.05) and negative association with Ca++ (R = -0.340, p < 0.05) in the PHPT group; MVC was positively associated with one-third radius aBMD (R = 0.360, p < 0.05) and negatively with age, BMI and myostatin (R = -0.390, -0.340 and -0.450, p < 0.05) in the group of healthy women. The linear model using BMI, Ca++, P, 25 (OH) D, PTH, myostatin, and aBMD as covariates showed that one-third radius aBMD was positively associated with MVC in PHPT patients (p < 0.02) and in healthy subjects (p < 0.001). Additionally, serum PTH and myostatin were negatively associated with MVC in healthy subjects (p < 0.03 and p < 0.01). The linear model showed that surgery was associated with an increase in MVC (p < 0.05) in PHPT patients after 24 months, all other variables being equal and by controlling for baseline values of MVC. Handgrip strength is significantly impaired in postmenopausal women with PHPT. Some common mechanisms influencing muscle function exist in PHPT and in healthy subjects; they are associated with the reduced aBMD at cortical sites. Hypercalcemia seems to be one of the main determinants of impairment in muscle strength in PHPT, while no role is played by myostatin.","PeriodicalId":93913,"journal":{"name":"Bone","volume":"1 1","pages":"116604"},"PeriodicalIF":0.0,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43246826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Qian Chen, Ziteng Wang, Chengyu Yang, Baochen Li, Xingxing Ren, Chao Liu, Lei Xi
Osteogenesis and angiogenesis are essential for bone homeostasis and repair. Newly formed vessels convey osteogenic progenitors during bone regeneration. However, the lack of continuous and label-free visualization of the bone microvasculature has resulted in little understanding of the neovascular dynamics. Here, we take advantage of optical-resolution photoacoustic microscopy (ORPAM) for label-free, intravital, long-term observation of the bone vascular dynamics, including angiogenesis, remodeling and quantified angiogenic effect of locally-applied vascular endothelial growth factor (VEGF) in the murine tibial defect model. We employed ex vivo confocal microscopy and micro-computed tomography (micro-CT) imaging to verify the positive role of VEGF treatment. VEGF treatment increased the concentration of total hemoglobin, vascular branching, and vascular density, which correlated with more osteoprogenitors and increased bone formation within the defect. These data demonstrated ORPAM as a useful imaging tool that detected functional capillaries to understand hemodynamics, and revealed the effectiveness of locally delivered therapeutic agents with sufficient sensitivity, contributing to the understanding of spatiotemporal regulatory mechanisms on blood vessels during bone regeneration.
{"title":"High resolution intravital photoacoustic microscopy reveals VEGF-induced bone regeneration in mouse tibia.","authors":"Qian Chen, Ziteng Wang, Chengyu Yang, Baochen Li, Xingxing Ren, Chao Liu, Lei Xi","doi":"10.2139/ssrn.4163454","DOIUrl":"https://doi.org/10.2139/ssrn.4163454","url":null,"abstract":"Osteogenesis and angiogenesis are essential for bone homeostasis and repair. Newly formed vessels convey osteogenic progenitors during bone regeneration. However, the lack of continuous and label-free visualization of the bone microvasculature has resulted in little understanding of the neovascular dynamics. Here, we take advantage of optical-resolution photoacoustic microscopy (ORPAM) for label-free, intravital, long-term observation of the bone vascular dynamics, including angiogenesis, remodeling and quantified angiogenic effect of locally-applied vascular endothelial growth factor (VEGF) in the murine tibial defect model. We employed ex vivo confocal microscopy and micro-computed tomography (micro-CT) imaging to verify the positive role of VEGF treatment. VEGF treatment increased the concentration of total hemoglobin, vascular branching, and vascular density, which correlated with more osteoprogenitors and increased bone formation within the defect. These data demonstrated ORPAM as a useful imaging tool that detected functional capillaries to understand hemodynamics, and revealed the effectiveness of locally delivered therapeutic agents with sufficient sensitivity, contributing to the understanding of spatiotemporal regulatory mechanisms on blood vessels during bone regeneration.","PeriodicalId":93913,"journal":{"name":"Bone","volume":"1 1","pages":"116631"},"PeriodicalIF":0.0,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42209944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Osteopetrosis (OPT) is a life-threatening disease characterized by increased bone mass caused by diminished osteoclast function/differentiation. The autosomal recessive forms, caused by biallelic variants in implicated genes, usually present in infancy. Without treatment, autosomal recessive OPTs are usually fatal within the first 10 years of life [1]. Here, we review the clinical features and associated pathophysiology of the autosomal recessive OPT. A greater understanding of these rare disorders will advance early diagnosis and optimal management.
{"title":"Phenotype-autosomal recessive osteopetrosis.","authors":"Nishitha R Pillai, A. Aggarwal, Paulina Orchard","doi":"10.2139/ssrn.4132889","DOIUrl":"https://doi.org/10.2139/ssrn.4132889","url":null,"abstract":"Osteopetrosis (OPT) is a life-threatening disease characterized by increased bone mass caused by diminished osteoclast function/differentiation. The autosomal recessive forms, caused by biallelic variants in implicated genes, usually present in infancy. Without treatment, autosomal recessive OPTs are usually fatal within the first 10 years of life [1]. Here, we review the clinical features and associated pathophysiology of the autosomal recessive OPT. A greater understanding of these rare disorders will advance early diagnosis and optimal management.","PeriodicalId":93913,"journal":{"name":"Bone","volume":"1 1","pages":"116577"},"PeriodicalIF":0.0,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45411040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mingjie Zhao, Justin J. Tse, Michael T. Kuczynski, Scott C. Brunet, Ryan Yan, K. Engelke, M. Peters, J. V. D. van den Bergh, B. van Rietbergen, K. Stok, C. Barnabe, Y. Pauchard, S. Manske
Identification of bone erosions and quantification of erosion volume is important for rheumatoid arthritis diagnosis, and can add important information to evaluate disease progression and treatment effects. High-resolution peripheral quantitative computed tomography (HR-pQCT) is well suited for this purpose, however analysis methods are not widely available. The purpose of this study was to develop an open-source software tool for the identification and quantification of bone erosions using images acquired by HR-pQCT. The collection of modules, Bone Analysis Modules (BAM) - Erosion, implements previously published erosion analysis techniques as modules in 3D Slicer, an open-source image processing and visualization tool. BAM includes a module to automatically identify cortical interruptions, from which erosions are manually selected, and a hybrid module that combines morphological and level set operations to quantify the volume of bone erosions. HR-pQCT images of the second and third metacarpophalangeal (MCP) joints were acquired in patients with RA (XtremeCT, n = 14, XtremeCTII, n = 22). The number of cortical interruptions detected by BAM-Erosion agreed strongly with the previously published cortical interruption detection algorithm for both XtremeCT (r2 = 0.85) and XtremeCTII (r2 = 0.87). Erosion volume assessment by BAM-Erosion agreed strongly (r2 = 0.95) with the Medical Image Analysis Framework. BAM-Erosion provides an open-source erosion analysis tool that produces comparable results to previously published algorithms, with improved options for visualization. The strength of the tool is that it implements multiple image processing algorithms for erosion analysis on a single, widely available, open-source platform that can accommodate future updates.
骨糜烂的识别和糜烂体积的量化对类风湿关节炎的诊断是重要的，并且可以为评估疾病进展和治疗效果提供重要信息。高分辨率外围定量计算机断层扫描(HR-pQCT)非常适合这一目的，然而分析方法并不广泛可用。本研究的目的是开发一种开源软件工具，用于利用HR-pQCT获得的图像识别和定量骨侵蚀。骨骼分析模块(BAM) -侵蚀模块的集合实现了先前发布的侵蚀分析技术，作为3D切片器的模块，这是一个开源的图像处理和可视化工具。BAM包括一个自动识别皮质中断的模块，从中手动选择侵蚀，以及一个结合形态学和水平集操作的混合模块，以量化骨侵蚀的体积。获得RA患者第二和第三掌指(MCP)关节的HR-pQCT图像(XtremeCT, n = 14,XtremeCTII, n = 22)。BAM-Erosion检测到的皮质中断数量与之前发表的XtremeCT (r2 = 0.85)和XtremeCTII (r2 = 0.87)的皮质中断检测算法非常吻合。BAM-Erosion的侵蚀体积评估与医学图像分析框架非常一致(r2 = 0.95)。BAM-Erosion提供了一个开源的侵蚀分析工具，可以产生与以前发布的算法相当的结果，并改进了可视化选项。该工具的优势在于，它在一个广泛可用的开源平台上实现了用于侵蚀分析的多种图像处理算法，该平台可以适应未来的更新。
{"title":"Open-source image analysis tool for the identification and quantification of cortical interruptions and bone erosions in high-resolution peripheral quantitative computed tomography images of patients with rheumatoid arthritis.","authors":"Mingjie Zhao, Justin J. Tse, Michael T. Kuczynski, Scott C. Brunet, Ryan Yan, K. Engelke, M. Peters, J. V. D. van den Bergh, B. van Rietbergen, K. Stok, C. Barnabe, Y. Pauchard, S. Manske","doi":"10.2139/ssrn.4169782","DOIUrl":"https://doi.org/10.2139/ssrn.4169782","url":null,"abstract":"Identification of bone erosions and quantification of erosion volume is important for rheumatoid arthritis diagnosis, and can add important information to evaluate disease progression and treatment effects. High-resolution peripheral quantitative computed tomography (HR-pQCT) is well suited for this purpose, however analysis methods are not widely available. The purpose of this study was to develop an open-source software tool for the identification and quantification of bone erosions using images acquired by HR-pQCT. The collection of modules, Bone Analysis Modules (BAM) - Erosion, implements previously published erosion analysis techniques as modules in 3D Slicer, an open-source image processing and visualization tool. BAM includes a module to automatically identify cortical interruptions, from which erosions are manually selected, and a hybrid module that combines morphological and level set operations to quantify the volume of bone erosions. HR-pQCT images of the second and third metacarpophalangeal (MCP) joints were acquired in patients with RA (XtremeCT, n = 14, XtremeCTII, n = 22). The number of cortical interruptions detected by BAM-Erosion agreed strongly with the previously published cortical interruption detection algorithm for both XtremeCT (r2 = 0.85) and XtremeCTII (r2 = 0.87). Erosion volume assessment by BAM-Erosion agreed strongly (r2 = 0.95) with the Medical Image Analysis Framework. BAM-Erosion provides an open-source erosion analysis tool that produces comparable results to previously published algorithms, with improved options for visualization. The strength of the tool is that it implements multiple image processing algorithms for erosion analysis on a single, widely available, open-source platform that can accommodate future updates.","PeriodicalId":93913,"journal":{"name":"Bone","volume":"1 1","pages":"116571"},"PeriodicalIF":0.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45012783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Quentin Meslier, Nicole DiMauro, Priya Somanchi, Sarah Nano, S. Shefelbine
Mechanical stimulation is critical to maintaining bone mass and strength. Strain has been commonly thought of as the mechanical stimulus driving bone adaptation. However, numerous studies have hypothesized that fluid flow in the lacunar-canalicular system plays a role in mechanoadaptation. The role of fluid flow compared to strain magnitude on bone remodeling has yet to be characterized. This study aimed to determine the contribution of fluid flow velocity compared to strain on bone adaptation. We used finite element modeling to design in vivo experiments, manipulating strain and fluid flow contributions. Using a uniaxial compression tibia model in mice, we demonstrated that high fluid flow velocity results in significant bone adaptation even under low strain magnitude. In contrast, high strain magnitude paired with low fluid velocity does not trigger a bone response. These findings support previous hypotheses stating that fluid flow is the principal mechanical stimulus driving bone adaptation. Moreover, they give new insights regarding bone adaptative response and provide new pathways toward treatment against age-related mechanosensitivity loss in bone.
{"title":"Manipulating load-induced fluid flow in vivo to promote bone adaptation.","authors":"Quentin Meslier, Nicole DiMauro, Priya Somanchi, Sarah Nano, S. Shefelbine","doi":"10.2139/ssrn.4168547","DOIUrl":"https://doi.org/10.2139/ssrn.4168547","url":null,"abstract":"Mechanical stimulation is critical to maintaining bone mass and strength. Strain has been commonly thought of as the mechanical stimulus driving bone adaptation. However, numerous studies have hypothesized that fluid flow in the lacunar-canalicular system plays a role in mechanoadaptation. The role of fluid flow compared to strain magnitude on bone remodeling has yet to be characterized. This study aimed to determine the contribution of fluid flow velocity compared to strain on bone adaptation. We used finite element modeling to design in vivo experiments, manipulating strain and fluid flow contributions. Using a uniaxial compression tibia model in mice, we demonstrated that high fluid flow velocity results in significant bone adaptation even under low strain magnitude. In contrast, high strain magnitude paired with low fluid velocity does not trigger a bone response. These findings support previous hypotheses stating that fluid flow is the principal mechanical stimulus driving bone adaptation. Moreover, they give new insights regarding bone adaptative response and provide new pathways toward treatment against age-related mechanosensitivity loss in bone.","PeriodicalId":93913,"journal":{"name":"Bone","volume":"1 1","pages":"116547"},"PeriodicalIF":0.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47154860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Komal Waqas, Jinluan Chen, Tianqi Lu, Bram van der Eerden, F. Rivadeneira, A. Uitterlinden, T. Voortman, M. Zillikens
Studies on mice have shown a relationship between dietary intake of advanced glycation end-products (dAGEs) and deterioration of musculoskeletal health, but human studies are absent. We investigated the relationship between dietary intake of carboxymethyllysine (dCML) - an AGE prototype - and risk of sarcopenia at baseline and after 5 years of follow-up and a single evaluation of physical frailty in participants from the population-based Rotterdam Study. Appendicular lean mass (ALM) was obtained using insight dual-energy X-ray absorptiometry and hand grip strength (HGS) using a hydraulic hand dynamometer. Subjects with both low ALM and weak HGS were classified as having sarcopenia. Frailty (yes/no) was defined by presence of ≥3 and pre-frailty by presence of 1 or 2 components namely, exhaustion, weakness, slowness, weight loss or low physical activity. dCML was calculated using a food frequency questionnaire and dAGE databases. Logistic regression analysis was used to evaluate the odds of physical frailty and prevalent sarcopenia at baseline and follow-up and incident sarcopenia. 2782 participants with an age 66.4 ± 9.9 years and dCML intake 3.3 ± 1.3 mg/day, had data on sarcopenia at both time points. Of whom 84 had sarcopenia at baseline and 73 developed sarcopenia at follow-up. We observed an association of one SD increase in dCML intake with prevalent sarcopenia at baseline [odds ratio, OR = 1.27 (1.01-1.59)] and no association of dCML with incident sarcopenia at 5-year follow-up [OR = 1.12 (0.86-1.44)]. For frailty we analyzed 3577 participants, of whom 1972 were pre-frail and 158 were frail. We observed no association of dCML with either pre-frailty [OR = 0.99 (0.91-1.07)] or frailty [OR = 1.01 (0.83-1.22)] when non-frail subjects were used as reference. Our results show an association of dAGEs with sarcopenia cross-sectionally but not longitudinally where inconclusive findings are observed possibly due to a very low incidence of sarcopenia. There was no association with frailty cross-sectionally.
{"title":"Dietary advanced glycation end-products (dAGEs) intake and its relation to sarcopenia and frailty - The Rotterdam Study.","authors":"Komal Waqas, Jinluan Chen, Tianqi Lu, Bram van der Eerden, F. Rivadeneira, A. Uitterlinden, T. Voortman, M. Zillikens","doi":"10.2139/ssrn.4088382","DOIUrl":"https://doi.org/10.2139/ssrn.4088382","url":null,"abstract":"Studies on mice have shown a relationship between dietary intake of advanced glycation end-products (dAGEs) and deterioration of musculoskeletal health, but human studies are absent. We investigated the relationship between dietary intake of carboxymethyllysine (dCML) - an AGE prototype - and risk of sarcopenia at baseline and after 5 years of follow-up and a single evaluation of physical frailty in participants from the population-based Rotterdam Study. Appendicular lean mass (ALM) was obtained using insight dual-energy X-ray absorptiometry and hand grip strength (HGS) using a hydraulic hand dynamometer. Subjects with both low ALM and weak HGS were classified as having sarcopenia. Frailty (yes/no) was defined by presence of ≥3 and pre-frailty by presence of 1 or 2 components namely, exhaustion, weakness, slowness, weight loss or low physical activity. dCML was calculated using a food frequency questionnaire and dAGE databases. Logistic regression analysis was used to evaluate the odds of physical frailty and prevalent sarcopenia at baseline and follow-up and incident sarcopenia. 2782 participants with an age 66.4 ± 9.9 years and dCML intake 3.3 ± 1.3 mg/day, had data on sarcopenia at both time points. Of whom 84 had sarcopenia at baseline and 73 developed sarcopenia at follow-up. We observed an association of one SD increase in dCML intake with prevalent sarcopenia at baseline [odds ratio, OR = 1.27 (1.01-1.59)] and no association of dCML with incident sarcopenia at 5-year follow-up [OR = 1.12 (0.86-1.44)]. For frailty we analyzed 3577 participants, of whom 1972 were pre-frail and 158 were frail. We observed no association of dCML with either pre-frailty [OR = 0.99 (0.91-1.07)] or frailty [OR = 1.01 (0.83-1.22)] when non-frail subjects were used as reference. Our results show an association of dAGEs with sarcopenia cross-sectionally but not longitudinally where inconclusive findings are observed possibly due to a very low incidence of sarcopenia. There was no association with frailty cross-sectionally.","PeriodicalId":93913,"journal":{"name":"Bone","volume":"1 1","pages":"116564"},"PeriodicalIF":0.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41579454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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