The basis for increased fracture risk in type 2 diabetes (T2DM) is not well understood. In this multi-ethnic, population-based study (n = 565), we investigated bone microstructure, trabecular plate/rod morphology, and mineralization in women with T2DM (n = 175) with and without fracture using a second-generation HRpQCT and individual trabecula segmentation and mineralization (ITS; ITM). Covariate-adjusted aBMD was 3.0%-6.5% higher at all sites (all p<.005) in T2DM vs controls. By HRpQCT, T2DM had higher covariate-adjusted trabecular vBMD (5.3%-6.4%) and number (3.8%-5.1%) and greater cortical area at the radius and tibia. Covariate-adjusted cortical porosity was 10.0% higher at the tibia only in T2DM vs controls, but failure load did not differ. Among women with T2DM, those with adult atraumatic fracture (n = 59) had 5.2%-8.5% lower adjusted aBMD at all sites by DXA compared with those without fracture (n = 103). By HRpQCT, those with fracture had lower adjusted total vBMD and smaller cortical area (10.2%-16.1%), lower cortical thickness (10.5-15.8%) and lower cortical vBMD associated with 18.1 and 17.2% lower failure load at the radius and tibia, respectively (all p<.05); plate volume and thickness were 5.7% and 4.7% lower, respectively, (p<.05) while rod volume fraction was 12.8% higher in the fracture group at the tibia only. Sodium glucose cotransporter 2 inhibitor users (SGLT2i; n = 19), tended to have lower radial rod tissue mineral density by ITS (p=.06). GLP1 agonist users (n = 19) had trabecular deficits at both sites and higher cortical porosity and larger pores at the distal tibia. In summary, T2DM is associated with increased cortical porosity while those with T2DM and fracture have more marked cortical deficits and fewer trabecular plates associated with lower failure load.
{"title":"Fractures in women with type 2 diabetes are associated with marked deficits in cortical parameters and trabecular plates.","authors":"Sanchita Agarwal, Carmen Germosen, Isabella Rosillo, Mariana Bucovsky, Ivelisse Colon, Nayoung Kil, Zexi Wang, Andreea Dinescu, Xiang-Dong Edward Guo, Marcella Walker","doi":"10.1093/jbmr/zjae091","DOIUrl":"10.1093/jbmr/zjae091","url":null,"abstract":"<p><p>The basis for increased fracture risk in type 2 diabetes (T2DM) is not well understood. In this multi-ethnic, population-based study (n = 565), we investigated bone microstructure, trabecular plate/rod morphology, and mineralization in women with T2DM (n = 175) with and without fracture using a second-generation HRpQCT and individual trabecula segmentation and mineralization (ITS; ITM). Covariate-adjusted aBMD was 3.0%-6.5% higher at all sites (all p<.005) in T2DM vs controls. By HRpQCT, T2DM had higher covariate-adjusted trabecular vBMD (5.3%-6.4%) and number (3.8%-5.1%) and greater cortical area at the radius and tibia. Covariate-adjusted cortical porosity was 10.0% higher at the tibia only in T2DM vs controls, but failure load did not differ. Among women with T2DM, those with adult atraumatic fracture (n = 59) had 5.2%-8.5% lower adjusted aBMD at all sites by DXA compared with those without fracture (n = 103). By HRpQCT, those with fracture had lower adjusted total vBMD and smaller cortical area (10.2%-16.1%), lower cortical thickness (10.5-15.8%) and lower cortical vBMD associated with 18.1 and 17.2% lower failure load at the radius and tibia, respectively (all p<.05); plate volume and thickness were 5.7% and 4.7% lower, respectively, (p<.05) while rod volume fraction was 12.8% higher in the fracture group at the tibia only. Sodium glucose cotransporter 2 inhibitor users (SGLT2i; n = 19), tended to have lower radial rod tissue mineral density by ITS (p=.06). GLP1 agonist users (n = 19) had trabecular deficits at both sites and higher cortical porosity and larger pores at the distal tibia. In summary, T2DM is associated with increased cortical porosity while those with T2DM and fracture have more marked cortical deficits and fewer trabecular plates associated with lower failure load.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11337576/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141305038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Linyi Liu, Phuong T Le, J Patrizia Stohn, Hanghang Liu, Wangyang Ying, Roland Baron, Clifford J Rosen
Calorie restriction (CR) can lead to weight loss and decreased substrate availability for bone cells. Ultimately, this can lead to impaired peak bone acquisition in children and adolescence and bone loss in adults. But the mechanisms that drive diet-induced bone loss in humans are not well characterized. To explore those in greater detail, we examined the impact of 30% CR for 4 and 8 wk in both male and female 8-wk-old C57BL/6 J mice. Body composition, areal bone mineral density (aBMD), skeletal microarchitecture by micro-CT, histomorphometric parameters, and in vitro trajectories of osteoblast and adipocyte differentiation were examined. After 8 wk, CR mice lost weight and exhibited lower femoral and whole-body aBMD vs ad libitum (AL) mice. By micro-CT, CR mice had lower cortical bone area fraction vs AL mice, but males had preserved trabecular bone parameters and females showed increased bone volume fraction compared to AL mice. Histomorphometric analysis revealed that CR mice had a profound suppression in trabecular as well as endocortical and periosteal bone formation in addition to reduced bone resorption compared to AL mice. Bone marrow adipose tissue was significantly increased in CR mice. In vitro, the pace of adipogenesis in bone marrow stem cells was greatly accelerated with higher markers of adipocyte differentiation and more oil red O staining, whereas osteogenic differentiation was reduced. qRT-PCR and western blotting suggested that the expression of Wnt16 and the canonical β-catenin pathway was compromised during CR. In sum, CR causes impaired peak cortical bone mass due to a profound suppression in bone remodeling. The increase in marrow adipocytes in vitro and in vivo is related to both progenitor recruitment and adipogenesis in the face of nutrient insufficiency. Long-term CR may lead to lower bone mass principally in the cortical envelope, possibly due to impaired Wnt signaling.
卡路里限制(CR)会导致体重减轻和骨细胞基质供应减少。最终,这会导致儿童和青春期骨质获取峰值受损以及成人骨质流失。但是,饮食诱发人类骨质流失的机制还不十分明确。为了更详细地探讨这些机制,我们研究了在 8 周大的 C57BL/6 J 雄性和雌性小鼠中连续 4 周和 8 周限制 30% 热量的影响。我们检测了小鼠的身体成分、骨矿物质密度(aBMD)、微计算机断层扫描(micro-CT)显示的骨骼微结构、组织形态计量学参数以及体外成骨细胞和脂肪细胞分化轨迹。与自由饮食(AL)小鼠相比,4周和8周后,CR小鼠体重减轻,股骨和全身aBMD降低。显微 CT 显示,CR 小鼠的皮质骨面积分数比 AL 小鼠低,但与 AL 小鼠相比,雄性小鼠的骨小梁参数保持不变,雌性小鼠的骨体积分数在 8 周后有所增加。组织形态计量分析表明,与 AL 小鼠相比,CR 小鼠的骨小梁、皮质内和骨膜骨形成受到严重抑制,骨吸收也有所减少。与 AL 小鼠相比,CR 小鼠的骨髓脂肪组织明显增加。在体外,骨髓干细胞的脂肪生成速度大大加快,脂肪细胞分化的标记物更高,油红 O 染色更多,而成骨分化却减少了。总之,由于骨重塑受到严重抑制,CR导致峰值皮质骨量受损。体外和体内骨髓脂肪细胞的增加与祖细胞招募和营养不足情况下的脂肪生成有关。长期热量限制可能会导致骨量降低,主要是在皮质包膜,这可能是由于Wnt信号受损所致。
{"title":"Calorie restriction in mice impairs cortical but not trabecular peak bone mass by suppressing bone remodeling.","authors":"Linyi Liu, Phuong T Le, J Patrizia Stohn, Hanghang Liu, Wangyang Ying, Roland Baron, Clifford J Rosen","doi":"10.1093/jbmr/zjae104","DOIUrl":"10.1093/jbmr/zjae104","url":null,"abstract":"<p><p>Calorie restriction (CR) can lead to weight loss and decreased substrate availability for bone cells. Ultimately, this can lead to impaired peak bone acquisition in children and adolescence and bone loss in adults. But the mechanisms that drive diet-induced bone loss in humans are not well characterized. To explore those in greater detail, we examined the impact of 30% CR for 4 and 8 wk in both male and female 8-wk-old C57BL/6 J mice. Body composition, areal bone mineral density (aBMD), skeletal microarchitecture by micro-CT, histomorphometric parameters, and in vitro trajectories of osteoblast and adipocyte differentiation were examined. After 8 wk, CR mice lost weight and exhibited lower femoral and whole-body aBMD vs ad libitum (AL) mice. By micro-CT, CR mice had lower cortical bone area fraction vs AL mice, but males had preserved trabecular bone parameters and females showed increased bone volume fraction compared to AL mice. Histomorphometric analysis revealed that CR mice had a profound suppression in trabecular as well as endocortical and periosteal bone formation in addition to reduced bone resorption compared to AL mice. Bone marrow adipose tissue was significantly increased in CR mice. In vitro, the pace of adipogenesis in bone marrow stem cells was greatly accelerated with higher markers of adipocyte differentiation and more oil red O staining, whereas osteogenic differentiation was reduced. qRT-PCR and western blotting suggested that the expression of Wnt16 and the canonical β-catenin pathway was compromised during CR. In sum, CR causes impaired peak cortical bone mass due to a profound suppression in bone remodeling. The increase in marrow adipocytes in vitro and in vivo is related to both progenitor recruitment and adipogenesis in the face of nutrient insufficiency. Long-term CR may lead to lower bone mass principally in the cortical envelope, possibly due to impaired Wnt signaling.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11337945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141597972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yizhong Jenny Hu, Y Eric Yu, Herbert J Cooper, Roshan P Shah, Jeffrey A Geller, X Lucas Lu, Elizabeth Shane, Joan Bathon, Nancy E Lane, X Edward Guo
Knee osteoarthritis (OA), characterized by multiple joint tissue degenerations, remains a significant clinical challenge. Recent evidence suggests that crosstalk within the osteochondral unit may drive OA progression. Although structural-biomechanical properties of bone and cartilage have been studied, potential interaction within the osteochondral unit in the context of OA has yet to be investigated. We performed comprehensive structural and biomechanical quantification of the cartilage, subchondral bone plate (SBP), and subchondral trabecular bone (STB) using 101 osteochondral cores collected from tibial plateaus of 12 control human cadavers (CT, 5 male/7 female) and 19 patients undergoing total knee replacement (OA, 6 male/13 female). For each sample, we quantified SBP microstructure, plate-and-rod morphological properties of the STB using individual trabecula segmentation, and morphological and compositional properties of the articular cartilage. We also performed indentation testing on each compartment of the osteochondral unit to extract the respective structural-mechanical properties. Cartilage thickness was lower in moderate and severe OA regions, while Osteoarthritis Research Society International score was higher only in severe OA regions. GAG content did not change in any OA region. Aggregate and shear moduli were lower only in severe OA regions, while permeability was lower only in moderate OA regions. In the SBP, thickness and tissue mineral density were higher in moderate and severe OA regions. Tissue modulus of STB was lower in moderate OA regions despite a thicker and more mineralized SBP; this deterioration was not observed in severe OA regions. Regression analysis revealed strong correlations between cartilage and STB properties in CT; these correlations were also found in moderate OA regions but were not observed in severe OA regions. In summary, our findings comprehensively characterize the human OA osteochondral unit. Importantly, uncoupling cartilage and subchondral bone structural-mechanical properties may be a hallmark of OA.
膝关节骨关节炎(OA)以多种关节组织退化为特征,仍然是一项重大的临床挑战。最近的证据表明,骨软骨单元内的串扰可能会推动 OA 的发展。虽然人们已经对骨和软骨的结构-生物力学特性进行了研究,但对骨软骨单元在 OA 背景下的潜在相互作用尚未进行研究。我们使用从 12 例对照人体尸体(CT,5 例男性/7 例女性)和 19 例接受全膝关节置换术的患者(OA,6 例男性/13 例女性)的胫骨平台上采集的 101 个骨软骨核心,对软骨、软骨下骨板和软骨下小梁骨进行了全面的结构和生物力学量化。我们对每个样本的软骨下骨板微观结构、软骨下小梁骨的板棒形态特性(使用单个小梁分割)以及关节软骨的形态和成分特性进行了量化。我们还对骨软骨单位的每个分区进行了压痕测试,以提取各自的结构力学特性。软骨厚度在中度和重度OA区域较低,而OARSI评分仅在重度OA区域较高。任何OA区域的凝胶体含量均无变化。只有在重度 OA 区域,集聚模量和剪切模量较低,而只有在中度 OA 区域,渗透性较低。在软骨下骨板中,中度和重度 OA 区域的厚度和 TMD 较高。软骨下骨小梁的组织模量在中度 OA 区域较低,尽管软骨下骨板更厚且矿化程度更高;而在重度 OA 区域则未观察到这种恶化。回归分析显示,CT 中软骨和软骨下小梁骨的特性之间存在很强的相关性;这些相关性在中度 OA 区域也有发现,但在重度 OA 区域没有观察到。总之,我们的研究结果全面描述了人类 OA 骨软骨单元的特征。重要的是,软骨和软骨下骨结构-力学性能的不耦合可能是 OA 的一个标志。
{"title":"Mechanical and structural properties of articular cartilage and subchondral bone in human osteoarthritic knees.","authors":"Yizhong Jenny Hu, Y Eric Yu, Herbert J Cooper, Roshan P Shah, Jeffrey A Geller, X Lucas Lu, Elizabeth Shane, Joan Bathon, Nancy E Lane, X Edward Guo","doi":"10.1093/jbmr/zjae094","DOIUrl":"10.1093/jbmr/zjae094","url":null,"abstract":"<p><p>Knee osteoarthritis (OA), characterized by multiple joint tissue degenerations, remains a significant clinical challenge. Recent evidence suggests that crosstalk within the osteochondral unit may drive OA progression. Although structural-biomechanical properties of bone and cartilage have been studied, potential interaction within the osteochondral unit in the context of OA has yet to be investigated. We performed comprehensive structural and biomechanical quantification of the cartilage, subchondral bone plate (SBP), and subchondral trabecular bone (STB) using 101 osteochondral cores collected from tibial plateaus of 12 control human cadavers (CT, 5 male/7 female) and 19 patients undergoing total knee replacement (OA, 6 male/13 female). For each sample, we quantified SBP microstructure, plate-and-rod morphological properties of the STB using individual trabecula segmentation, and morphological and compositional properties of the articular cartilage. We also performed indentation testing on each compartment of the osteochondral unit to extract the respective structural-mechanical properties. Cartilage thickness was lower in moderate and severe OA regions, while Osteoarthritis Research Society International score was higher only in severe OA regions. GAG content did not change in any OA region. Aggregate and shear moduli were lower only in severe OA regions, while permeability was lower only in moderate OA regions. In the SBP, thickness and tissue mineral density were higher in moderate and severe OA regions. Tissue modulus of STB was lower in moderate OA regions despite a thicker and more mineralized SBP; this deterioration was not observed in severe OA regions. Regression analysis revealed strong correlations between cartilage and STB properties in CT; these correlations were also found in moderate OA regions but were not observed in severe OA regions. In summary, our findings comprehensively characterize the human OA osteochondral unit. Importantly, uncoupling cartilage and subchondral bone structural-mechanical properties may be a hallmark of OA.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141417001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yingkang Huang, Mingchao Zhang, Jun Zhang, Siying Liu, Dapei Li, Zigang Qiao, Haiping Yao, Qin Shi, Xiaozhong Zhou, Feng Ma
Type I interferons (IFN-I) are pleiotropic factors endowed with multiple activities that play important roles in innate and adaptive immunity. Although many studies indicate that IFN-I inducers exert favorable effects on broad-spectrum antivirus, immunomodulation, and anti-tumor activities by inducing endogenous IFN-I and IFN-stimulated genes, their function in bone homeostasis still needs further exploration. Here, our study demonstrates 2 distinct IFN-I inducers, diABZI and poly(I:C), as potential therapeutics to alleviate osteolysis and osteoporosis. First, IFN-I inducers suppress the genes that control osteoclast (OC) differentiation and activity in vitro. Moreover, diABZI alleviates bone loss in Ti particle-induced osteolysis and ovariectomized -induced osteoporosis in vivo by inhibiting OC differentiation and function. In addition, the inhibitory effects of IFN-I inducers on OC differentiation are not observed in macrophages derived from Ifnar1-/-mice, which indicate that the suppressive effect of IFN-I inducers on OC is IFNAR-dependent. Mechanistically, RNAi-mediated silencing of IRF7 and IFIT3 in OC precursors impairs the suppressive effect of the IFN-I inducers on OC differentiation. Taken together, these results demonstrate that IFN-I inducers play a protective role in bone turnover by limiting osteoclastogenesis and bone resorption through the induction of OC-specific mediators via the IFN-I signaling pathway.
{"title":"diABZI and poly(I:C) inhibit osteoclastic bone resorption by inducing IRF7 and IFIT3.","authors":"Yingkang Huang, Mingchao Zhang, Jun Zhang, Siying Liu, Dapei Li, Zigang Qiao, Haiping Yao, Qin Shi, Xiaozhong Zhou, Feng Ma","doi":"10.1093/jbmr/zjae093","DOIUrl":"10.1093/jbmr/zjae093","url":null,"abstract":"<p><p>Type I interferons (IFN-I) are pleiotropic factors endowed with multiple activities that play important roles in innate and adaptive immunity. Although many studies indicate that IFN-I inducers exert favorable effects on broad-spectrum antivirus, immunomodulation, and anti-tumor activities by inducing endogenous IFN-I and IFN-stimulated genes, their function in bone homeostasis still needs further exploration. Here, our study demonstrates 2 distinct IFN-I inducers, diABZI and poly(I:C), as potential therapeutics to alleviate osteolysis and osteoporosis. First, IFN-I inducers suppress the genes that control osteoclast (OC) differentiation and activity in vitro. Moreover, diABZI alleviates bone loss in Ti particle-induced osteolysis and ovariectomized -induced osteoporosis in vivo by inhibiting OC differentiation and function. In addition, the inhibitory effects of IFN-I inducers on OC differentiation are not observed in macrophages derived from Ifnar1-/-mice, which indicate that the suppressive effect of IFN-I inducers on OC is IFNAR-dependent. Mechanistically, RNAi-mediated silencing of IRF7 and IFIT3 in OC precursors impairs the suppressive effect of the IFN-I inducers on OC differentiation. Taken together, these results demonstrate that IFN-I inducers play a protective role in bone turnover by limiting osteoclastogenesis and bone resorption through the induction of OC-specific mediators via the IFN-I signaling pathway.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11337579/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141316268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Oliver Lehmann, Olga Mineeva, Dinara Veshchezerova, HansJörg Häuselmann, Laura Guyer, Stephan Reichenbach, Thomas Lehmann, Olga Demler, Judith Everts-Graber
Fracture prediction is essential in managing patients with osteoporosis and is an integral component of many fracture prevention guidelines. We aimed to identify the most relevant clinical fracture risk factors in contemporary populations by training and validating short- and long-term fracture risk prediction models in 2 cohorts. We used traditional and machine learning survival models to predict risks of vertebral, hip, and any fractures on the basis of clinical risk factors, T-scores, and treatment history among participants in a nationwide Swiss Osteoporosis Registry (N = 5944 postmenopausal women, median follow-up of 4.1 yr between January 2015 and October 2022; a total of 1190 fractures during follow-up). The independent validation cohort comprised 5474 postmenopausal women from the UK Biobank with 290 incident fractures during follow-up. Uno's C-index and the time-dependent area under the receiver operating characteristics curve were calculated to evaluate the performance of different machine learning models (Random survival forest and eXtreme Gradient Boosting). In the independent validation set, the C-index was 0.74 [0.58, 0.86] for vertebral fractures, 0.83 [0.7, 0.94] for hip fractures, and 0.63 [0.58, 0.69] for any fractures at year 2, and these values further increased for longer estimations of up to 7 yr. In comparison, the 10-yr fracture probability calculated with FRAX Switzerland was 0.60 [0.55, 0.64] for major osteoporotic fractures and 0.62 [0.49, 0.74] for hip fractures. The most important variables identified with Shapley additive explanations values were age, T-scores, and prior fractures, while number of falls was an important predictor of hip fractures. Performances of both traditional and machine learning models showed similar C-indices. We conclude that fracture risk can be improved by including the lumbar spine T-score, trabecular bone score, numbers of falls and recent fractures, and treatment information has a significant impact on fracture prediction.
{"title":"Fracture risk prediction in postmenopausal women with traditional and machine learning models in a nationwide, prospective cohort study in Switzerland with validation in the UK Biobank.","authors":"Oliver Lehmann, Olga Mineeva, Dinara Veshchezerova, HansJörg Häuselmann, Laura Guyer, Stephan Reichenbach, Thomas Lehmann, Olga Demler, Judith Everts-Graber","doi":"10.1093/jbmr/zjae089","DOIUrl":"10.1093/jbmr/zjae089","url":null,"abstract":"<p><p>Fracture prediction is essential in managing patients with osteoporosis and is an integral component of many fracture prevention guidelines. We aimed to identify the most relevant clinical fracture risk factors in contemporary populations by training and validating short- and long-term fracture risk prediction models in 2 cohorts. We used traditional and machine learning survival models to predict risks of vertebral, hip, and any fractures on the basis of clinical risk factors, T-scores, and treatment history among participants in a nationwide Swiss Osteoporosis Registry (N = 5944 postmenopausal women, median follow-up of 4.1 yr between January 2015 and October 2022; a total of 1190 fractures during follow-up). The independent validation cohort comprised 5474 postmenopausal women from the UK Biobank with 290 incident fractures during follow-up. Uno's C-index and the time-dependent area under the receiver operating characteristics curve were calculated to evaluate the performance of different machine learning models (Random survival forest and eXtreme Gradient Boosting). In the independent validation set, the C-index was 0.74 [0.58, 0.86] for vertebral fractures, 0.83 [0.7, 0.94] for hip fractures, and 0.63 [0.58, 0.69] for any fractures at year 2, and these values further increased for longer estimations of up to 7 yr. In comparison, the 10-yr fracture probability calculated with FRAX Switzerland was 0.60 [0.55, 0.64] for major osteoporotic fractures and 0.62 [0.49, 0.74] for hip fractures. The most important variables identified with Shapley additive explanations values were age, T-scores, and prior fractures, while number of falls was an important predictor of hip fractures. Performances of both traditional and machine learning models showed similar C-indices. We conclude that fracture risk can be improved by including the lumbar spine T-score, trabecular bone score, numbers of falls and recent fractures, and treatment information has a significant impact on fracture prediction.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141246796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Natalie K Y Wee, Narelle E McGregor, Emma C Walker, Ingrid J Poulton, Michelle Kieu Mi Dang, Jonathan H Gooi, Wayne A Phillips, Natalie A Sims
Intracellular phosphoinositide 3-kinase (PI3K) signaling is activated by multiple bone-active receptors. Genetic mutations activating PI3K signaling are associated with clinical syndromes of tissue overgrowth in multiple organs, often including the skeleton. While one formation is increased by removing the PI3K inhibitor (phosphatase and TENsin homolog deleted on chromosome 10 (PTEN)), the effect of direct PI3K activation in the osteoblast lineage has not been reported. We introduced a known gain-of-function mutation in Pik3ca, the gene encoding the p110α catalytic subunit of PI3K, in osteocytes and late osteoblasts using the dentin matrix protein-1 Cre (Dmp1Cre) mouse and assessed the skeletal phenotype. Femur shape was grossly normal, but cortical thickness was significantly greater in both male and female Dmp1Cre.Pik3caH1047R mice, leading to almost doubled bone strength at 12 wk of age. Both sexes had smaller marrow areas from 6 wk of age. Female mice also exhibited greater cross-sectional area, which continued to increase until 24 wk of age, resulting in a further increase in bone strength. Although both male and female mice had increased endocortical mineralizing surface, only female mice had increased periosteal mineralizing surface. The bone formed in the Dmp1Cre.Pik3caH1047R mice showed no increase in intracortical remodeling nor any defect in cortical bone consolidation. In contrast, on both endocortical and periosteal surfaces, there was more lamellar bone formation, including highly organized osteocyte networks extending along the entire surface at a greater thickness than in control mice. In conclusion, direct activation of PI3Kα in cells targeted by Dmp1Cre leads to high cortical bone mass and strength with abundant lamellar cortical bone in female and male mice with no increase in intracortical remodeling. This differs from the effect of PTEN deletion in the same cells, suggesting that activating PI3Kα in osteoblasts and osteocytes may be a more suitable target to promote formation of lamellar bone.
{"title":"Direct activation of PI3K in osteoblasts and osteocytes strengthens murine bone through sex-specific actions on cortical surfaces.","authors":"Natalie K Y Wee, Narelle E McGregor, Emma C Walker, Ingrid J Poulton, Michelle Kieu Mi Dang, Jonathan H Gooi, Wayne A Phillips, Natalie A Sims","doi":"10.1093/jbmr/zjae102","DOIUrl":"10.1093/jbmr/zjae102","url":null,"abstract":"<p><p>Intracellular phosphoinositide 3-kinase (PI3K) signaling is activated by multiple bone-active receptors. Genetic mutations activating PI3K signaling are associated with clinical syndromes of tissue overgrowth in multiple organs, often including the skeleton. While one formation is increased by removing the PI3K inhibitor (phosphatase and TENsin homolog deleted on chromosome 10 (PTEN)), the effect of direct PI3K activation in the osteoblast lineage has not been reported. We introduced a known gain-of-function mutation in Pik3ca, the gene encoding the p110α catalytic subunit of PI3K, in osteocytes and late osteoblasts using the dentin matrix protein-1 Cre (Dmp1Cre) mouse and assessed the skeletal phenotype. Femur shape was grossly normal, but cortical thickness was significantly greater in both male and female Dmp1Cre.Pik3caH1047R mice, leading to almost doubled bone strength at 12 wk of age. Both sexes had smaller marrow areas from 6 wk of age. Female mice also exhibited greater cross-sectional area, which continued to increase until 24 wk of age, resulting in a further increase in bone strength. Although both male and female mice had increased endocortical mineralizing surface, only female mice had increased periosteal mineralizing surface. The bone formed in the Dmp1Cre.Pik3caH1047R mice showed no increase in intracortical remodeling nor any defect in cortical bone consolidation. In contrast, on both endocortical and periosteal surfaces, there was more lamellar bone formation, including highly organized osteocyte networks extending along the entire surface at a greater thickness than in control mice. In conclusion, direct activation of PI3Kα in cells targeted by Dmp1Cre leads to high cortical bone mass and strength with abundant lamellar cortical bone in female and male mice with no increase in intracortical remodeling. This differs from the effect of PTEN deletion in the same cells, suggesting that activating PI3Kα in osteoblasts and osteocytes may be a more suitable target to promote formation of lamellar bone.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141496517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rita Patel, Andrew Judge, Antony Johansen, Muhammad K Javaid, Xavier L Griffin, Tim Chesser, Jill Griffin, Elsa M R Marques, Yoav Ben-Shlomo, Celia L Gregson
Patients who sustain a hip fracture are known to be at imminent refracture risk. Their complex multidisciplinary rehabilitation needs to include falls prevention and anti-osteoporosis medication (AOM) to prevent such fractures. This study aimed to determine which hospital-level organizational factors predict prescription of post-hip fracture AOM and refracture risk. A cohort of 178 757 patients aged ≥60 yr who sustained a hip fracture in England and Wales (2016-2019) was examined and followed for 1 yr. Patient-level hospital admission datasets from 172 hospitals, the National Hip Fracture Database, and mortality data were linked to 71 metrics extracted from 18 hospital-level organizational reports. Multilevel models determined organizational factors, independent of patient case-mix, associated with (1) AOM prescription and (2) refracture (by ICD10 coding). Patients were mean (SD) 82.7 (8.6) yr old, 71% female, with 18% admitted from care homes. Overall, 101 735 (57%) were prescribed AOM during admission, while 50 354 (28%) died during 1-yr follow-up, 12 240 (7%) refractured. Twelve organizational factors were associated with AOM prescription, for example, orthogeriatrician-led care compared to traditional care models (odds ratio [OR] 4.65 [95% CI, 2.25-9.59]); AOM was 9% (95% CI, 6%-13%) more likely to be prescribed in hospitals providing routine bone health assessment to all patients. Refracture occurred at median 126 d (IQR 59-234). Eight organizational factors were associated with refracture risk; hospitals providing orthogeriatrician assessment to all patients within 72 h of admission had an 18% (95% CI, 2%-31%) lower refracture risk, weekend physiotherapy provision had an 8% (95% CI, 3%-14%) lower risk, and where occupational therapists attended clinical governance meetings, a 7% (95% CI, 2%-12%) lower risk. Delays initiating post-discharge community rehabilitation were associated with a 15% (95% CI, 3%-29%) greater refracture risk. These novel, national findings highlight the importance of orthogeriatrician, physiotherapist, and occupational therapist involvement in secondary fracture prevention post hip fracture; notably, fracture risk reductions were seen within 12 mo of hip fracture.
{"title":"Following hip fracture, hospital organizational factors associated with prescription of anti-osteoporosis medication on discharge, to address imminent refracture risk: a record-linkage study.","authors":"Rita Patel, Andrew Judge, Antony Johansen, Muhammad K Javaid, Xavier L Griffin, Tim Chesser, Jill Griffin, Elsa M R Marques, Yoav Ben-Shlomo, Celia L Gregson","doi":"10.1093/jbmr/zjae100","DOIUrl":"10.1093/jbmr/zjae100","url":null,"abstract":"<p><p>Patients who sustain a hip fracture are known to be at imminent refracture risk. Their complex multidisciplinary rehabilitation needs to include falls prevention and anti-osteoporosis medication (AOM) to prevent such fractures. This study aimed to determine which hospital-level organizational factors predict prescription of post-hip fracture AOM and refracture risk. A cohort of 178 757 patients aged ≥60 yr who sustained a hip fracture in England and Wales (2016-2019) was examined and followed for 1 yr. Patient-level hospital admission datasets from 172 hospitals, the National Hip Fracture Database, and mortality data were linked to 71 metrics extracted from 18 hospital-level organizational reports. Multilevel models determined organizational factors, independent of patient case-mix, associated with (1) AOM prescription and (2) refracture (by ICD10 coding). Patients were mean (SD) 82.7 (8.6) yr old, 71% female, with 18% admitted from care homes. Overall, 101 735 (57%) were prescribed AOM during admission, while 50 354 (28%) died during 1-yr follow-up, 12 240 (7%) refractured. Twelve organizational factors were associated with AOM prescription, for example, orthogeriatrician-led care compared to traditional care models (odds ratio [OR] 4.65 [95% CI, 2.25-9.59]); AOM was 9% (95% CI, 6%-13%) more likely to be prescribed in hospitals providing routine bone health assessment to all patients. Refracture occurred at median 126 d (IQR 59-234). Eight organizational factors were associated with refracture risk; hospitals providing orthogeriatrician assessment to all patients within 72 h of admission had an 18% (95% CI, 2%-31%) lower refracture risk, weekend physiotherapy provision had an 8% (95% CI, 3%-14%) lower risk, and where occupational therapists attended clinical governance meetings, a 7% (95% CI, 2%-12%) lower risk. Delays initiating post-discharge community rehabilitation were associated with a 15% (95% CI, 3%-29%) greater refracture risk. These novel, national findings highlight the importance of orthogeriatrician, physiotherapist, and occupational therapist involvement in secondary fracture prevention post hip fracture; notably, fracture risk reductions were seen within 12 mo of hip fracture.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11337946/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141578437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vertebral compression fractures (VCFs) are common and indicate a high future risk of additional osteoporotic fractures. However, many VCFs are unreported by radiologists, and even if reported, many patients do not receive treatment. The purpose of the study was to evaluate a new artificial intelligence (AI) algorithm for the detection of VCFs and to assess the prevalence of reported and unreported VCFs. This retrospective cohort study included patients over age 60 yr with an abdominal CT between January 18, 2019 and January 18, 2020. Images and radiology reports were reviewed to identify reported and unreported VCFs, and the images were processed by an AI algorithm. For reported VCFs, the electronic health records were reviewed regarding subsequent osteoporosis screening and treatment. Totally, 1112 patients were included. Of these, 187 patients (16.8%) had a VCF, of which 62 had an incident VCF and 49 had a previously unknown prevalent VCF. The radiologist reporting rate of these VCFs was 30% (33/111). For moderate and severe (grade 2-3) VCF, the AI algorithm had 85.2% sensitivity, 92.3% specificity, 57.8% positive predictive value, and 98.1% negative predictive value. Three of 30 patients with reported VCFs started osteoporosis treatment within a year. The AI algorithm had high accuracy for the detection of VCFs and could be very useful in increasing the detection rate of VCFs, as there was a substantial underdiagnosis of VCFs. However, as undertreatment in reported cases was substantial, to fully realize the potential of AI, changes to the management pathway outside of the radiology department are imperative.
{"title":"Vertebral compression fractures at abdominal CT: underdiagnosis, undertreatment, and evaluation of an AI algorithm.","authors":"Peder Wiklund, David Buchebner, Mats Geijer","doi":"10.1093/jbmr/zjae096","DOIUrl":"10.1093/jbmr/zjae096","url":null,"abstract":"<p><p>Vertebral compression fractures (VCFs) are common and indicate a high future risk of additional osteoporotic fractures. However, many VCFs are unreported by radiologists, and even if reported, many patients do not receive treatment. The purpose of the study was to evaluate a new artificial intelligence (AI) algorithm for the detection of VCFs and to assess the prevalence of reported and unreported VCFs. This retrospective cohort study included patients over age 60 yr with an abdominal CT between January 18, 2019 and January 18, 2020. Images and radiology reports were reviewed to identify reported and unreported VCFs, and the images were processed by an AI algorithm. For reported VCFs, the electronic health records were reviewed regarding subsequent osteoporosis screening and treatment. Totally, 1112 patients were included. Of these, 187 patients (16.8%) had a VCF, of which 62 had an incident VCF and 49 had a previously unknown prevalent VCF. The radiologist reporting rate of these VCFs was 30% (33/111). For moderate and severe (grade 2-3) VCF, the AI algorithm had 85.2% sensitivity, 92.3% specificity, 57.8% positive predictive value, and 98.1% negative predictive value. Three of 30 patients with reported VCFs started osteoporosis treatment within a year. The AI algorithm had high accuracy for the detection of VCFs and could be very useful in increasing the detection rate of VCFs, as there was a substantial underdiagnosis of VCFs. However, as undertreatment in reported cases was substantial, to fully realize the potential of AI, changes to the management pathway outside of the radiology department are imperative.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141430935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nephropathic cystinosis is an orphan autosomal recessive lysosomal storage disease characterized by a deficiency of cystinosin, a cystine transporter protein, leading to tissue damage, primarily in the kidney and cornea. With the introduction of cystine-depleting therapy with cysteamine and the possibility to survive to adulthood, new challenges of skeletal complications are a concern, with sparse data available regarding bone development. The aim of the current study was to gain more information on bone density and geometry in these patients. Fifty-one patients (29 males, 22 females) with genetically proven nephropathic cystinosis were clinically evaluated with a medical history, physical examination, grip strength measurements, and biochemical and imaging studies. Bone mineral density, bone geometry, and muscle cross sectional area were measured, and muscle was evaluated. Results were compared with age- and gender-specific reference data. Z-scores for height (mean [M] = -1.75, standard deviation [SD] = 1.43), weight (M = -1.67, SD = 1.29), and BMI (M = -0.98, SD = 1.29) were lower than reference data. Medullary cross-sectional area (CSA) and cortical density z-scores were not compromised (M = 0.12, SD = 1.56 and M = -0.25, SD = 1.63, respectively), but cortical CSA z-scores and Strength-Strain Index (SSI) were reduced (M = -2.16, SD = 1.08, M = -2.07, SD = 1.08). Muscular deficits were reflected by reduced z-scores for muscle CSA (M = -2.43, SD = 1.27) and grip strength (M = -3.01, SD = 1.10), along with jump force (34% lower than reference value). Multiple regression analyses indicated an association of muscle mass with medullary CSA and SSI, but not with cortical CSA. While bone density parameters were normal, bone geometry was altered, resulting in a thinner cortex with possible impact on bone strength. Muscle weakness be partially responsible for altered bone geometry and could provide a potential treatment target.
肾病性胱氨酸病是一种孤儿型常染色体隐性遗传溶酶体储积病,其特点是缺乏胱氨酸转运蛋白--胱抑素,从而导致组织损伤,主要是肾脏和角膜损伤。随着半胱胺胱氨酸消耗疗法的引入以及患者有可能存活至成年,骨骼并发症带来的新挑战令人担忧,而有关骨骼发育的数据却十分稀少。本研究旨在获得更多有关这些患者骨密度和几何形状的信息。研究人员对 51 名经遗传证实患有肾病性胱氨酸沉积症的患者(29 名男性,22 名女性)进行了临床评估,包括病史、体格检查、握力测量、生化和影像学研究。对骨质密度、骨骼几何形状和肌肉横截面积进行了测量,并对肌肉进行了评估。结果与特定年龄和性别的参考数据进行了比较。身高(平均值[M] = -1.75, 标准差[SD] = 1.43)、体重(平均值[M] = -1.67, 标准差[SD] = 1.29)和体重指数(平均值[M] = -0.98,标准差[SD] = 1.29)的 Z 值均低于参考数据。髓质横截面积(CSA)和皮质密度 z 值没有受到影响(分别为中=0.12,标度=1.56 和中=-0.25,标度=1.63),但皮质 CSA z 值和力量应变指数(SSI)有所降低(中=-2.16,标度=1.08,中=-2.07,标度=1.08)。肌肉缺损表现为肌肉CSA(中值=-2.43,标度值=1.27)和握力(中值=-3.01,标度值=1.10)的z值降低,以及跳跃力(比参考值低34%)降低。多元回归分析表明,肌肉质量与髓质CSA和SSI有关,但与皮质CSA无关。虽然骨密度参数正常,但骨骼几何形状发生了改变,导致皮质变薄,可能会影响骨强度。肌肉无力是导致骨几何形状改变的部分原因,可能成为潜在的治疗目标。
{"title":"Cortical impairment and reduced muscle mass in children and young adults with nephropathic cystinosis.","authors":"Susanne Bechtold-Dalla Pozza, Simon Lemster, Nadine Herzig, Katharina Vill, Ilja Dubinski, Katharina Hohenfellner","doi":"10.1093/jbmr/zjae092","DOIUrl":"10.1093/jbmr/zjae092","url":null,"abstract":"<p><p>Nephropathic cystinosis is an orphan autosomal recessive lysosomal storage disease characterized by a deficiency of cystinosin, a cystine transporter protein, leading to tissue damage, primarily in the kidney and cornea. With the introduction of cystine-depleting therapy with cysteamine and the possibility to survive to adulthood, new challenges of skeletal complications are a concern, with sparse data available regarding bone development. The aim of the current study was to gain more information on bone density and geometry in these patients. Fifty-one patients (29 males, 22 females) with genetically proven nephropathic cystinosis were clinically evaluated with a medical history, physical examination, grip strength measurements, and biochemical and imaging studies. Bone mineral density, bone geometry, and muscle cross sectional area were measured, and muscle was evaluated. Results were compared with age- and gender-specific reference data. Z-scores for height (mean [M] = -1.75, standard deviation [SD] = 1.43), weight (M = -1.67, SD = 1.29), and BMI (M = -0.98, SD = 1.29) were lower than reference data. Medullary cross-sectional area (CSA) and cortical density z-scores were not compromised (M = 0.12, SD = 1.56 and M = -0.25, SD = 1.63, respectively), but cortical CSA z-scores and Strength-Strain Index (SSI) were reduced (M = -2.16, SD = 1.08, M = -2.07, SD = 1.08). Muscular deficits were reflected by reduced z-scores for muscle CSA (M = -2.43, SD = 1.27) and grip strength (M = -3.01, SD = 1.10), along with jump force (34% lower than reference value). Multiple regression analyses indicated an association of muscle mass with medullary CSA and SSI, but not with cortical CSA. While bone density parameters were normal, bone geometry was altered, resulting in a thinner cortex with possible impact on bone strength. Muscle weakness be partially responsible for altered bone geometry and could provide a potential treatment target.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141305037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
La Li, Dai Li, Jingxian Zhu, Yiqun Wang, Feng Zhao, Jin Cheng, Rocky S Tuan, Xiaoqing Hu, Yingfang Ao
In previous studies, we have demonstrated that stress response-induced high glucocorticoid levels could be the underlying cause of traumatic heterotopic ossification (HO), and we have developed a glucocorticoid-induced ectopic mineralization (EM) mouse model by systemic administration of a high dose of dexamethasone (DEX) to animals with muscle injury induced by cardiotoxin injection. In this model, dystrophic calcification (DC) developed into HO in a cell autonomous manner. However, it is not clear how DC is formed after DEX treatment. Therefore, in this study, we aimed to explore how glucocorticoids initiate muscle EM at a cellular and molecular level. We showed that DEX treatment inhibited inflammatory cell infiltration into injured muscle but inflammatory cytokine production in the muscle was significantly increased, suggesting that other non-inflammatory muscle cell types may regulate the inflammatory response and the muscle repair process. Accompanying this phenotype, transforming growth factor β1 (TGF-β1) expression in fibro-adipogenic progenitors (FAPs) was greatly downregulated. Since TGF-β1 is a strong immune suppressor and FAP's regulatory role has a large impact on muscle repair, we hypothesized that downregulation of TGF-β1 in FAPs after DEX treatment resulted in this hyperinflammatory state and subsequent failed muscle repair and EM formation. To test our hypothesis, we utilized a transgenic mouse model to specifically knockout Tgfb1 gene in PDGFRα-positive FAPs to investigate if the transgenic mice could recapitulate the phenotype that was induced by DEX treatment. Our results showed that the transgenic mice completely phenocopied this hyperinflammatory state and spontaneously developed EM following muscle injury. On the contrary, therapeutics that enhanced TGF-β1 signaling in FAPs inhibited the inflammatory response and attenuated muscle EM. In summary, these results indicate that FAPs-derived TGF-β1 is a key molecule in regulating muscle inflammatory response and subsequent EM, and that glucocorticoids exert their effect via downregulating TGF-β1 in FAPs.
{"title":"Downregulation of TGF-β1 in fibro-adipogenic progenitors initiates muscle ectopic mineralization.","authors":"La Li, Dai Li, Jingxian Zhu, Yiqun Wang, Feng Zhao, Jin Cheng, Rocky S Tuan, Xiaoqing Hu, Yingfang Ao","doi":"10.1093/jbmr/zjae097","DOIUrl":"10.1093/jbmr/zjae097","url":null,"abstract":"<p><p>In previous studies, we have demonstrated that stress response-induced high glucocorticoid levels could be the underlying cause of traumatic heterotopic ossification (HO), and we have developed a glucocorticoid-induced ectopic mineralization (EM) mouse model by systemic administration of a high dose of dexamethasone (DEX) to animals with muscle injury induced by cardiotoxin injection. In this model, dystrophic calcification (DC) developed into HO in a cell autonomous manner. However, it is not clear how DC is formed after DEX treatment. Therefore, in this study, we aimed to explore how glucocorticoids initiate muscle EM at a cellular and molecular level. We showed that DEX treatment inhibited inflammatory cell infiltration into injured muscle but inflammatory cytokine production in the muscle was significantly increased, suggesting that other non-inflammatory muscle cell types may regulate the inflammatory response and the muscle repair process. Accompanying this phenotype, transforming growth factor β1 (TGF-β1) expression in fibro-adipogenic progenitors (FAPs) was greatly downregulated. Since TGF-β1 is a strong immune suppressor and FAP's regulatory role has a large impact on muscle repair, we hypothesized that downregulation of TGF-β1 in FAPs after DEX treatment resulted in this hyperinflammatory state and subsequent failed muscle repair and EM formation. To test our hypothesis, we utilized a transgenic mouse model to specifically knockout Tgfb1 gene in PDGFRα-positive FAPs to investigate if the transgenic mice could recapitulate the phenotype that was induced by DEX treatment. Our results showed that the transgenic mice completely phenocopied this hyperinflammatory state and spontaneously developed EM following muscle injury. On the contrary, therapeutics that enhanced TGF-β1 signaling in FAPs inhibited the inflammatory response and attenuated muscle EM. In summary, these results indicate that FAPs-derived TGF-β1 is a key molecule in regulating muscle inflammatory response and subsequent EM, and that glucocorticoids exert their effect via downregulating TGF-β1 in FAPs.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141417000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}