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}
S. Rui, T. Kubota, Y. Ohata, Kenichi Yamamoto, M. Fujiwara, S. Takeyari, K. Ozono
BACKGROUND Phosphate is indispensable in osteogenesis and mineralization. However, mechanisms by which phosphate enhances osteogenic differentiation are not fully understood. In this study, we studied the effect of phosphate on osteogenic differentiation as well as signaling pathways induced by phosphate in the process. METHOD Induced human bone marrow-derived mesenchymal stem cells differentiation into osteoblasts by the change of media containing β-glycerophosphate (GP), 1 mM inorganic phosphate, or 3 mM inorganic phosphate (Pi). The differentiation of osteoblasts was verified by the expression of osteoblast differentiation markers and calcium deposition. RNA sequencing was performed to assess transcriptome in the early stage of osteogenic differentiation. RESULTS Osteogenic differentiation and mineralization were promoted in the 3 mM Pi group compared to those in the GP and 1 mM Pi groups on day 7 of culture. RNA sequencing revealed that the gene expressions involved in osteogenesis and the components in the Wnt signaling pathway was increased in 3 mM Pi group compared with those in the GP on day 7. Analysis with qPCR and Western blot suggested upregulation of components in the non-canonical Wnt signaling pathway, including WNT5b and phosphorylated-c-Jun in the 3 mM Pi group on day 7. WNT11 mRNA expression was increased in the 2 induction groups on day 7. Inhibition of WNT5b by siRNA experiment attenuated the components in non-canonical Wnt signaling expression, including WNT5b, WNT11 and ROR2 mRNA expression and phosphorylated-c-Jun protein expression. In addition, osteogenic differentiation and mineralization were partly decreased in 3 mM Pi group on day 7 by the inhibition of WNT5b. CONCLUSION Pi promoted osteogenic differentiation through the up-regulation of the non-canonical Wnt signaling pathway, including WNT5b, WNT11, p-c-Jun/c-Jun, in the early stage of differentiation. These findings provide a new perspective into the association of Pi and the non-canonical Wnt signaling pathway during osteogenic differentiation.
磷酸盐在成骨和矿化中是不可缺少的。然而，磷酸盐促进成骨分化的机制尚不完全清楚。在本研究中，我们研究了磷酸盐对成骨分化的影响以及在此过程中磷酸盐诱导的信号通路。方法通过改变含有β-甘油磷酸(GP)、1 mM无机磷酸盐或3 mM无机磷酸盐(Pi)的培养基，诱导人骨髓间充质干细胞向成骨细胞分化。成骨细胞分化标志物的表达和钙沉积证实成骨细胞的分化。通过RNA测序来评估成骨分化早期的转录组。结果在培养第7天，与GP和1 mM Pi组相比，3 mM Pi组促进了成骨分化和矿化。RNA测序结果显示，与GP组相比，3 mM Pi组在第7天的成骨相关基因和Wnt信号通路组分的表达增加。qPCR和Western blot分析显示，3 mM Pi组在第7天上调了非规范Wnt信号通路中的成分，包括WNT5b和磷酸化c- jun。在第7天，2个诱导组的WNT11 mRNA表达均升高。siRNA实验抑制WNT5b后，WNT5b、WNT11、ROR2 mRNA表达和磷酸化c- jun蛋白表达等非规范Wnt信号表达组分减弱。此外，3 mM Pi组在第7天通过抑制WNT5b部分抑制成骨分化和矿化。结论pi在分化早期通过上调WNT5b、WNT11、p-c-Jun/c-Jun等非规范Wnt信号通路促进成骨分化。这些发现为研究Pi与成骨分化过程中非规范Wnt信号通路的关联提供了新的视角。
{"title":"Phosphate promotes osteogenic differentiation through non-canonical Wnt signaling pathway in human mesenchymal stem cells.","authors":"S. Rui, T. Kubota, Y. Ohata, Kenichi Yamamoto, M. Fujiwara, S. Takeyari, K. Ozono","doi":"10.2139/ssrn.4145245","DOIUrl":"https://doi.org/10.2139/ssrn.4145245","url":null,"abstract":"BACKGROUND\u0000Phosphate is indispensable in osteogenesis and mineralization. However, mechanisms by which phosphate enhances osteogenic differentiation are not fully understood. In this study, we studied the effect of phosphate on osteogenic differentiation as well as signaling pathways induced by phosphate in the process.\u0000\u0000\u0000METHOD\u0000Induced human bone marrow-derived mesenchymal stem cells differentiation into osteoblasts by the change of media containing β-glycerophosphate (GP), 1 mM inorganic phosphate, or 3 mM inorganic phosphate (Pi). The differentiation of osteoblasts was verified by the expression of osteoblast differentiation markers and calcium deposition. RNA sequencing was performed to assess transcriptome in the early stage of osteogenic differentiation.\u0000\u0000\u0000RESULTS\u0000Osteogenic differentiation and mineralization were promoted in the 3 mM Pi group compared to those in the GP and 1 mM Pi groups on day 7 of culture. RNA sequencing revealed that the gene expressions involved in osteogenesis and the components in the Wnt signaling pathway was increased in 3 mM Pi group compared with those in the GP on day 7. Analysis with qPCR and Western blot suggested upregulation of components in the non-canonical Wnt signaling pathway, including WNT5b and phosphorylated-c-Jun in the 3 mM Pi group on day 7. WNT11 mRNA expression was increased in the 2 induction groups on day 7. Inhibition of WNT5b by siRNA experiment attenuated the components in non-canonical Wnt signaling expression, including WNT5b, WNT11 and ROR2 mRNA expression and phosphorylated-c-Jun protein expression. In addition, osteogenic differentiation and mineralization were partly decreased in 3 mM Pi group on day 7 by the inhibition of WNT5b.\u0000\u0000\u0000CONCLUSION\u0000Pi promoted osteogenic differentiation through the up-regulation of the non-canonical Wnt signaling pathway, including WNT5b, WNT11, p-c-Jun/c-Jun, in the early stage of differentiation. These findings provide a new perspective into the association of Pi and the non-canonical Wnt signaling pathway during osteogenic differentiation.","PeriodicalId":93913,"journal":{"name":"Bone","volume":"1 1","pages":"116525"},"PeriodicalIF":0.0,"publicationDate":"2022-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44031123","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}
Meghan M. Moran, F. Ko, L. Mesner, G. Calabrese, B. Al-Barghouthi, C. Farber, D. Sumner
There are over one million cases of failed bone repair in the U.S. annually, resulting in substantial patient morbidity and societal costs. Multiple candidate genes affecting bone traits such as bone mineral density have been identified in human subjects and animal models using genome-wide association studies (GWAS). This approach for understanding the genetic factors affecting bone repair is impractical in human subjects but could be performed in a model organism if there is sufficient variability and heritability in the bone regeneration response. Diversity Outbred (DO) mice, which have significant genetic diversity and have been used to examine multiple intact bone traits, would be an excellent possibility. Thus, we sought to evaluate the phenotypic distribution of bone regeneration, sex effects and heritability of intramembranous bone regeneration on day 7 following femoral marrow ablation in 47 12-week old DO mice (23 males, 24 females). Compared to a previous study using 4 inbred mouse strains, we found similar levels of variability in the amount of regenerated bone (coefficient of variation of 86 % v. 88 %) with approximately the same degree of heritability (0.42 v. 0.49). There was a trend toward more bone regeneration in males than females. The amount of regenerated bone was either weakly or not correlated with bone mass at intact sites, suggesting that the genetic factors responsible for bone regeneration and intact bone phenotypes are at least partially independent. In conclusion, we demonstrate that DO mice exhibit variation and heritability of intramembranous bone regeneration that will be suitable for future GWAS.
在美国，每年有超过一百万例骨修复失败的病例，导致大量的患者发病率和社会成本。利用全基因组关联研究(GWAS)在人类受试者和动物模型中发现了影响骨性状(如骨矿物质密度)的多个候选基因。这种理解影响骨修复的遗传因素的方法在人类受试者中是不切实际的，但如果在骨再生反应中有足够的可变性和遗传性，则可以在模式生物中进行。近亲繁殖(DO)小鼠具有显著的遗传多样性，并已被用于检查多个完整的骨骼特征，将是一个很好的可能性。因此，我们试图评估47只12周龄DO小鼠(23只雄性，24只雌性)股骨骨髓消融后第7天骨再生的表型分布、性别效应和遗传力。与先前使用4种近交系小鼠的研究相比，我们发现再生骨量的可变性水平相似(变异系数为86 % vs . 88 %)，遗传度大致相同(0.42 vs . 0.49)。男性比女性有更多的骨再生趋势。再生骨的数量与完整部位的骨量或弱或不相关，这表明负责骨再生和完整骨表型的遗传因素至少部分独立。总之，我们证明DO小鼠表现出膜内骨再生的变异和遗传性，这将适合未来的GWAS。
{"title":"Intramembranous bone regeneration in diversity outbred mice is heritable.","authors":"Meghan M. Moran, F. Ko, L. Mesner, G. Calabrese, B. Al-Barghouthi, C. Farber, D. Sumner","doi":"10.2139/ssrn.4117253","DOIUrl":"https://doi.org/10.2139/ssrn.4117253","url":null,"abstract":"There are over one million cases of failed bone repair in the U.S. annually, resulting in substantial patient morbidity and societal costs. Multiple candidate genes affecting bone traits such as bone mineral density have been identified in human subjects and animal models using genome-wide association studies (GWAS). This approach for understanding the genetic factors affecting bone repair is impractical in human subjects but could be performed in a model organism if there is sufficient variability and heritability in the bone regeneration response. Diversity Outbred (DO) mice, which have significant genetic diversity and have been used to examine multiple intact bone traits, would be an excellent possibility. Thus, we sought to evaluate the phenotypic distribution of bone regeneration, sex effects and heritability of intramembranous bone regeneration on day 7 following femoral marrow ablation in 47 12-week old DO mice (23 males, 24 females). Compared to a previous study using 4 inbred mouse strains, we found similar levels of variability in the amount of regenerated bone (coefficient of variation of 86 % v. 88 %) with approximately the same degree of heritability (0.42 v. 0.49). There was a trend toward more bone regeneration in males than females. The amount of regenerated bone was either weakly or not correlated with bone mass at intact sites, suggesting that the genetic factors responsible for bone regeneration and intact bone phenotypes are at least partially independent. In conclusion, we demonstrate that DO mice exhibit variation and heritability of intramembranous bone regeneration that will be suitable for future GWAS.","PeriodicalId":93913,"journal":{"name":"Bone","volume":"1 1","pages":"116524"},"PeriodicalIF":0.0,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44068925","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}
The discovery that mutations in TCIRG1 (also known as Atp6i) gene are responsible for the majority of autosomal recessive osteopetrosis (ARO) forms in humans heralded a new era for comprehension of this heterogeneous rare bone disease. TCIRG1 gene encodes the a3 subunit, an essential isoform of the vacuolar ATPase proton pump involved in the acidification of the resorption lacuna and in secretory lysosome trafficking. The gene defects lead to inefficient bone resorption by unfunctional osteoclasts which are seen in abundance on bone marrow biopsy, delineating this form of ARO as 'osteoclast-rich'. Patients usually present in early childhood with features of extramedullary haematopoiesis (hepatosplenomegaly, anaemia, thrombocytopenia) due to bone marrow fibrosis, and cranial nerve encroachment (blindness in particular). Impaired gastric calcium uptake due to high pH causes the co-occurrence of rickets, described as "osteopetrorickets". Osteoclast dysfunction leads to early death if untreated and allogeneic haematopoietic stem cell transplantation is the treatment of choice. Combined studies in patients and mouse models carrying spontaneous (the oc/oc mouse) or targeted disruption of Atp6i (TCIRG1) gene have been instrumental for the insight into disease pathogenesis and for the development of novel cellular therapies exploiting gene correction.
{"title":"Osteoclast rich osteopetrosis due to defects in TCIRG1 gene.","authors":"Valentina Capo, M. Abinun, A. Villa","doi":"10.2139/ssrn.4138979","DOIUrl":"https://doi.org/10.2139/ssrn.4138979","url":null,"abstract":"The discovery that mutations in TCIRG1 (also known as Atp6i) gene are responsible for the majority of autosomal recessive osteopetrosis (ARO) forms in humans heralded a new era for comprehension of this heterogeneous rare bone disease. TCIRG1 gene encodes the a3 subunit, an essential isoform of the vacuolar ATPase proton pump involved in the acidification of the resorption lacuna and in secretory lysosome trafficking. The gene defects lead to inefficient bone resorption by unfunctional osteoclasts which are seen in abundance on bone marrow biopsy, delineating this form of ARO as 'osteoclast-rich'. Patients usually present in early childhood with features of extramedullary haematopoiesis (hepatosplenomegaly, anaemia, thrombocytopenia) due to bone marrow fibrosis, and cranial nerve encroachment (blindness in particular). Impaired gastric calcium uptake due to high pH causes the co-occurrence of rickets, described as \"osteopetrorickets\". Osteoclast dysfunction leads to early death if untreated and allogeneic haematopoietic stem cell transplantation is the treatment of choice. Combined studies in patients and mouse models carrying spontaneous (the oc/oc mouse) or targeted disruption of Atp6i (TCIRG1) gene have been instrumental for the insight into disease pathogenesis and for the development of novel cellular therapies exploiting gene correction.","PeriodicalId":93913,"journal":{"name":"Bone","volume":"1 1","pages":"116519"},"PeriodicalIF":0.0,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42539823","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}
F. Laskou, L. Westbury, N. Fuggle, N. Harvey, H. Patel, C. Cooper, K. Ward, E. Dennison
PURPOSE The age-related loss of skeletal muscle mass and strength is associated with adverse health outcomes. However, to date, peripheral quantitative computed tomography (pQCT)-derived muscle density has been little studied. We used a well characterised cohort of older adults to identify lifestyle and anthropometric determinants of pQCT-derived muscle density measured 11 years later, and to report relationships between pQCT-derived muscle density with history of falls and prevalent fractures. METHODS A lifestyle questionnaire was administered to 197 men and 178 women, aged 59-70 at baseline. After a median of 11.5 (IQR 10.9, 12.3) years, pQCT (Stratec XCT2000) of the radius and tibia was performed to measure forearm muscle density (FMD) and calf muscle density (CMD). Presence of falls and fractures since the age of 45 were determined through participant recall; vertebral fractures were also ascertained through vertebral fracture assessment using iDXA. Total hip BMD (TH aBMD) was assessed using DXA. Baseline characteristics in relation to muscle density at follow-up were examined using linear regression; associations between muscle density and prior falls and fractures were investigated using logistic regression. All analyses were adjusted for sex and age. RESULTS Mean (SD) age at muscle density measurement was 76.3 (2.6) years. Mean (SD) FMD was 79.9 (3.1) and 77.2 (3.2) among males and females, respectively; CMD was 80.7 (2.6) and 78.5 (2.6) among males and females, respectively. Significant sex-differences in muscle density were observed at each site (p < 0.001). Female sex, lower weight, and lower body mass index were associated (p < 0.05) with both lower FMD and CMD. Additional correlates of lower CMD included older age and shorter stature. Lifestyle measures were not associated with muscle density in this cohort. Lower FMD was related to increased risk of previous fracture (OR (95 % CI) per SD lower FMD: 1.42 (1.07, 1.89), p = 0.015) but not after adjustment for TH aBMD (p > 0.08). No significant relationships were seen between muscle density and falls. CONCLUSION Female sex, older age, and lower BMI were associated with subsequent lower muscle density in older community-dwelling adults. Lower FMD was related to increased risk of previous fracture. Changes in muscle density over time might precede adverse outcomes such as falls and fractures and may be a long-term predictor of frailty. It could be also suggested that muscle density could be a more clinically meaningful surrogate of functional decline and disability than muscle size or mass, but more studies are needed to support this notion.
{"title":"Determinants of muscle density and clinical outcomes: Findings from the Hertfordshire Cohort Study.","authors":"F. Laskou, L. Westbury, N. Fuggle, N. Harvey, H. Patel, C. Cooper, K. Ward, E. Dennison","doi":"10.2139/ssrn.4108552","DOIUrl":"https://doi.org/10.2139/ssrn.4108552","url":null,"abstract":"PURPOSE\u0000The age-related loss of skeletal muscle mass and strength is associated with adverse health outcomes. However, to date, peripheral quantitative computed tomography (pQCT)-derived muscle density has been little studied. We used a well characterised cohort of older adults to identify lifestyle and anthropometric determinants of pQCT-derived muscle density measured 11 years later, and to report relationships between pQCT-derived muscle density with history of falls and prevalent fractures.\u0000\u0000\u0000METHODS\u0000A lifestyle questionnaire was administered to 197 men and 178 women, aged 59-70 at baseline. After a median of 11.5 (IQR 10.9, 12.3) years, pQCT (Stratec XCT2000) of the radius and tibia was performed to measure forearm muscle density (FMD) and calf muscle density (CMD). Presence of falls and fractures since the age of 45 were determined through participant recall; vertebral fractures were also ascertained through vertebral fracture assessment using iDXA. Total hip BMD (TH aBMD) was assessed using DXA. Baseline characteristics in relation to muscle density at follow-up were examined using linear regression; associations between muscle density and prior falls and fractures were investigated using logistic regression. All analyses were adjusted for sex and age.\u0000\u0000\u0000RESULTS\u0000Mean (SD) age at muscle density measurement was 76.3 (2.6) years. Mean (SD) FMD was 79.9 (3.1) and 77.2 (3.2) among males and females, respectively; CMD was 80.7 (2.6) and 78.5 (2.6) among males and females, respectively. Significant sex-differences in muscle density were observed at each site (p < 0.001). Female sex, lower weight, and lower body mass index were associated (p < 0.05) with both lower FMD and CMD. Additional correlates of lower CMD included older age and shorter stature. Lifestyle measures were not associated with muscle density in this cohort. Lower FMD was related to increased risk of previous fracture (OR (95 % CI) per SD lower FMD: 1.42 (1.07, 1.89), p = 0.015) but not after adjustment for TH aBMD (p > 0.08). No significant relationships were seen between muscle density and falls.\u0000\u0000\u0000CONCLUSION\u0000Female sex, older age, and lower BMI were associated with subsequent lower muscle density in older community-dwelling adults. Lower FMD was related to increased risk of previous fracture. Changes in muscle density over time might precede adverse outcomes such as falls and fractures and may be a long-term predictor of frailty. It could be also suggested that muscle density could be a more clinically meaningful surrogate of functional decline and disability than muscle size or mass, but more studies are needed to support this notion.","PeriodicalId":93913,"journal":{"name":"Bone","volume":"1 1","pages":"116521"},"PeriodicalIF":0.0,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45526461","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}
The clinical and radiological variability seen in different forms of osteopetrosis, all due to impaired osteoclastic bone resorption, reflect many causal genes. Both defective differentiation of osteoclasts from hematopoietic stem cells as well as disturbed functioning of osteoclasts can be the underlying pathogenic mechanism. Pathogenic variants in PLEKHM1 and SNX10 can be classified among the latter as they impair vesicular transport within the osteoclast and therefore result in the absence of a ruffled border. Some of the typical radiological hallmarks of osteopetrosis can be seen, and most cases present as a relatively mild form segregating in an autosomal recessive mode of inheritance.
{"title":"Osteopetrosis associated with PLEKHM1 and SNX10 genes, both involved in osteoclast vesicular trafficking.","authors":"Yentl Huybrechts, W. Van Hul","doi":"10.2139/ssrn.4137168","DOIUrl":"https://doi.org/10.2139/ssrn.4137168","url":null,"abstract":"The clinical and radiological variability seen in different forms of osteopetrosis, all due to impaired osteoclastic bone resorption, reflect many causal genes. Both defective differentiation of osteoclasts from hematopoietic stem cells as well as disturbed functioning of osteoclasts can be the underlying pathogenic mechanism. Pathogenic variants in PLEKHM1 and SNX10 can be classified among the latter as they impair vesicular transport within the osteoclast and therefore result in the absence of a ruffled border. Some of the typical radiological hallmarks of osteopetrosis can be seen, and most cases present as a relatively mild form segregating in an autosomal recessive mode of inheritance.","PeriodicalId":93913,"journal":{"name":"Bone","volume":"1 1","pages":"116520"},"PeriodicalIF":0.0,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47301916","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}
I. Haider, A. Sawatsky, Ying Zhu, Rebecca Page, P. Kostenuik, S. Boyd, W. B. Edwards
Upper extremity fractures, including those at the humerus, are common among women with postmenopausal osteoporosis. Denosumab was shown to reduce humeral fractures in this population; however, no clinical or preclinical studies have quantified the effects of denosumab on humerus bone mineral density or bone microarchitecture changes. This study used micro-computed tomography (μCT) and computed tomography (CT), alongside image-based finite element (FE) models derived from both modalities, to quantify the effects of denosomab (DMAb) and alendronate (ALN) on humeral bone from acutely ovariectomized (OVX) cynomolgus monkeys. Animals were treated with 12 monthly injections of s.c. vehicle (VEH; n = 10), s.c. denosumab (DMAb; 25 mg/kg, n = 9), or i.v. alendronate (ALN; 50 μg/kg, n = 10). Two more groups received 6 months of VEH followed by 6 months of DMAb (VEH-DMAb; n = 7) or 6 months of ALN followed by 6 months of DMAb (ALN-DMAb; n = 9). After treatment, humeri were harvested and μCT was used to quantify tissue mineral density, trabecular morphology, and cortical porosity at the humeral head. Clinical CT imaging was also used to quantify trabecular and cortical bone mineral density (BMD) at the ultra-proximal, proximal, 1/5 proximal and midshaft of the bone. Finally, μCT-based FE models in compression, and CT-based FE models in compression, torsion, and bending, were developed to estimate differences in strength. Compared to VEH, groups that received DMAb at any time demonstrated lower cortical porosity and/or higher tissue mineral density via μCT; no effects on trabecular morphology were observed. FE estimated strength based on μCT was higher after 12-months DMAb (p = 0.020) and ALN-DMAb (p = 0.024) vs. VEH; respectively, FE predicted mean (SD) strength was 4649.88 (710.58) N, and 4621.10 (1050.16) N vs. 3309.4 (876.09) N. All antiresorptive treatments were associated with higher cortical BMD via CT at the 1/5 proximal and midshaft of the humerus; however, no differences in CT-based FE predicted strength were observed. Overall, these results help to explain the observed reductions in humeral fracture rate following DMAb treatment in women with postmenopausal osteoporosis.
{"title":"Denosumab treatment is associated with decreased cortical porosity and increased bone density and strength at the proximal humerus of ovariectomized cynomolgus monkeys.","authors":"I. Haider, A. Sawatsky, Ying Zhu, Rebecca Page, P. Kostenuik, S. Boyd, W. B. Edwards","doi":"10.2139/ssrn.4045829","DOIUrl":"https://doi.org/10.2139/ssrn.4045829","url":null,"abstract":"Upper extremity fractures, including those at the humerus, are common among women with postmenopausal osteoporosis. Denosumab was shown to reduce humeral fractures in this population; however, no clinical or preclinical studies have quantified the effects of denosumab on humerus bone mineral density or bone microarchitecture changes. This study used micro-computed tomography (μCT) and computed tomography (CT), alongside image-based finite element (FE) models derived from both modalities, to quantify the effects of denosomab (DMAb) and alendronate (ALN) on humeral bone from acutely ovariectomized (OVX) cynomolgus monkeys. Animals were treated with 12 monthly injections of s.c. vehicle (VEH; n = 10), s.c. denosumab (DMAb; 25 mg/kg, n = 9), or i.v. alendronate (ALN; 50 μg/kg, n = 10). Two more groups received 6 months of VEH followed by 6 months of DMAb (VEH-DMAb; n = 7) or 6 months of ALN followed by 6 months of DMAb (ALN-DMAb; n = 9). After treatment, humeri were harvested and μCT was used to quantify tissue mineral density, trabecular morphology, and cortical porosity at the humeral head. Clinical CT imaging was also used to quantify trabecular and cortical bone mineral density (BMD) at the ultra-proximal, proximal, 1/5 proximal and midshaft of the bone. Finally, μCT-based FE models in compression, and CT-based FE models in compression, torsion, and bending, were developed to estimate differences in strength. Compared to VEH, groups that received DMAb at any time demonstrated lower cortical porosity and/or higher tissue mineral density via μCT; no effects on trabecular morphology were observed. FE estimated strength based on μCT was higher after 12-months DMAb (p = 0.020) and ALN-DMAb (p = 0.024) vs. VEH; respectively, FE predicted mean (SD) strength was 4649.88 (710.58) N, and 4621.10 (1050.16) N vs. 3309.4 (876.09) N. All antiresorptive treatments were associated with higher cortical BMD via CT at the 1/5 proximal and midshaft of the humerus; however, no differences in CT-based FE predicted strength were observed. Overall, these results help to explain the observed reductions in humeral fracture rate following DMAb treatment in women with postmenopausal osteoporosis.","PeriodicalId":93913,"journal":{"name":"Bone","volume":"1 1","pages":"116517"},"PeriodicalIF":0.0,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47837907","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}
J. Everts‐Graber, S. Reichenbach, B. Gahl, H. Häuselmann, H. Ziswiler, U. Studer, Thomas Lehmann
BACKGROUND The rebound effect after denosumab discontinuation is lessened with subsequent zoledronate therapy. However, it is unclear whether this mitigation is sufficient after long-term denosumab treatment. OBJECTIVE This retrospective observational study analysed bone mineral density (BMD) and bone turnover marker (BTM) changes after denosumab therapy according to treatment duration and subsequent zoledronate regimen. METHODS We measured the outcomes of 282 women with postmenopausal osteoporosis who discontinued denosumab and received zoledronate 6 months later. In patients with longer denosumab therapy (≥5 years), BTMs were measured every 3 months and a second zoledronate infusion was administered if BTM levels increased by ≥2-fold. The BMD of all women was measured before denosumab therapy, at the last injection and 1 to 2 years after the first zoledronate. RESULTS Bone loss after switching from denosumab to zoledronate was higher in patients with 10 ± 2 denosumab injections (n = 84) compared to 5 ± 2 injections (n = 144, p < 0.001 for lumbar spine and femoral neck), but there was no further increase with treatment durations of ≥15 ± 2 injections (n = 54, p = 0.35 and p = 0.20, respectively). BTMs in patients with ≥10 denosumab injections were elevated 6 months after zoledronate in some patients, but not all. Twenty-four women received a second zoledronate dose 6 months after the first one. BTMs in these patients were subsequently lower, but bone loss at both the lumbar spine and hip was comparable to that in patients with only one zoledronate dose (p = 0.37 for lumbar spine and p = 0.97 for femoral neck). CONCLUSIONS Rebound-associated bone loss reached a plateau after denosumab treatment durations of 4-6 years, irrespective of the frequency of subsequent zoledronate therapy.
{"title":"Effects of zoledronate on bone mineral density and bone turnover after long-term denosumab therapy: Observations in a real-world setting.","authors":"J. Everts‐Graber, S. Reichenbach, B. Gahl, H. Häuselmann, H. Ziswiler, U. Studer, Thomas Lehmann","doi":"10.2139/ssrn.4106277","DOIUrl":"https://doi.org/10.2139/ssrn.4106277","url":null,"abstract":"BACKGROUND\u0000The rebound effect after denosumab discontinuation is lessened with subsequent zoledronate therapy. However, it is unclear whether this mitigation is sufficient after long-term denosumab treatment.\u0000\u0000\u0000OBJECTIVE\u0000This retrospective observational study analysed bone mineral density (BMD) and bone turnover marker (BTM) changes after denosumab therapy according to treatment duration and subsequent zoledronate regimen.\u0000\u0000\u0000METHODS\u0000We measured the outcomes of 282 women with postmenopausal osteoporosis who discontinued denosumab and received zoledronate 6 months later. In patients with longer denosumab therapy (≥5 years), BTMs were measured every 3 months and a second zoledronate infusion was administered if BTM levels increased by ≥2-fold. The BMD of all women was measured before denosumab therapy, at the last injection and 1 to 2 years after the first zoledronate.\u0000\u0000\u0000RESULTS\u0000Bone loss after switching from denosumab to zoledronate was higher in patients with 10 ± 2 denosumab injections (n = 84) compared to 5 ± 2 injections (n = 144, p < 0.001 for lumbar spine and femoral neck), but there was no further increase with treatment durations of ≥15 ± 2 injections (n = 54, p = 0.35 and p = 0.20, respectively). BTMs in patients with ≥10 denosumab injections were elevated 6 months after zoledronate in some patients, but not all. Twenty-four women received a second zoledronate dose 6 months after the first one. BTMs in these patients were subsequently lower, but bone loss at both the lumbar spine and hip was comparable to that in patients with only one zoledronate dose (p = 0.37 for lumbar spine and p = 0.97 for femoral neck).\u0000\u0000\u0000CONCLUSIONS\u0000Rebound-associated bone loss reached a plateau after denosumab treatment durations of 4-6 years, irrespective of the frequency of subsequent zoledronate therapy.","PeriodicalId":93913,"journal":{"name":"Bone","volume":"1 1","pages":"116498"},"PeriodicalIF":0.0,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42365535","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：