Pub Date : 2024-11-26DOI: 10.1016/j.bone.2024.117339
Sarah V. Mendoza , Kristina V. Wells , Deepa K. Murugesh , Nicholas R. Hum , Aimy Sebastian , Bria M. Gorman , Alice Wong , Benjamin Osipov , Blaine A. Christiansen , Gabriela G. Loots , Alexander G. Robling , Clare E. Yellowley , Damian C. Genetos
Skeletal fracture resistance emerges from multiple components of bone structure like microarchitecture, matrix mineralization, and organization. These characteristics are engendered via mechanisms like the hypoxia-inducible factors (HIF) pathway, involving two paralogs, HIF-1α and HIF-2α. Under normoxia, HIF-α is targeted for degradation via von-Hippel Lindau (VHL); hypoxia enables HIF-α stabilization and induction of target genes. We previously showed that osteocytic Vhl deletion or expression of degradation-resistant HIF-2α cDR female mice each produced high bone mass, whereas degradation-resistant osteocytic HIF-1α produced no overt phenotype. We report within that Vhl cKO increased bone strength, while HIF-2α cDR displayed markedly reduced bone strength below Cre-negative controls. This suggests that VHL and HIF-2α drive distinct responses that promote disparate effects on bone strength. Both Vhl deletion or HIF-2α accumulation generated two discrete bone morphologies: an outer lamellar cortex and a woven, poorly mineralized endocortex that imparted dramatically different functional outcomes. Our studies reveal novel influence of osteocytic HIF-2α signaling on collagen matrix organization, mineralization, and bone strength.
{"title":"Osteocytic oxygen sensing: Distinct impacts of VHL and HIF-2alpha on bone integrity","authors":"Sarah V. Mendoza , Kristina V. Wells , Deepa K. Murugesh , Nicholas R. Hum , Aimy Sebastian , Bria M. Gorman , Alice Wong , Benjamin Osipov , Blaine A. Christiansen , Gabriela G. Loots , Alexander G. Robling , Clare E. Yellowley , Damian C. Genetos","doi":"10.1016/j.bone.2024.117339","DOIUrl":"10.1016/j.bone.2024.117339","url":null,"abstract":"<div><div>Skeletal fracture resistance emerges from multiple components of bone structure like microarchitecture, matrix mineralization, and organization. These characteristics are engendered <em>via</em> mechanisms like the hypoxia-inducible factors (HIF) pathway, involving two paralogs, HIF-1α and HIF-2α. Under normoxia, HIF-α is targeted for degradation <em>via</em> von-Hippel Lindau (VHL); hypoxia enables HIF-α stabilization and induction of target genes. We previously showed that osteocytic Vhl deletion or expression of degradation-resistant HIF-2α cDR female mice each produced high bone mass, whereas degradation-resistant osteocytic HIF-1α produced no overt phenotype. We report within that Vhl cKO increased bone strength, while HIF-2α cDR displayed markedly reduced bone strength below Cre-negative controls. This suggests that VHL and HIF-2α drive distinct responses that promote disparate effects on bone strength. Both Vhl deletion or HIF-2α accumulation generated two discrete bone morphologies: an outer lamellar cortex and a woven, poorly mineralized endocortex that imparted dramatically different functional outcomes. Our studies reveal novel influence of osteocytic HIF-2α signaling on collagen matrix organization, mineralization, and bone strength.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"192 ","pages":"Article 117339"},"PeriodicalIF":3.5,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142741743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-20DOI: 10.1016/j.bone.2024.117336
Tsolmonbaatar Khurelbaatar , Leah Fisher , Lindsey Westover , Michael R. Doschak , Dan L. Romanyk
The age-based morphometric changes of cranial sutures are not well established, particularly in a quantitative manner. Most prior work utilized planar reslicing approaches to analyze sutures and the quantitative measurements of suture morphometry were limited to a short segment not following the true skull shape. The present study aimed to investigate the age-based morphometric changes of the coronal suture during normal growth of young rats using a novel curved-reslicing approach.
Longitudinal in vivo micro-computed tomography (μCT) scans were completed at five time points (7, 9, 11, 16 and 21 weeks of age) during normal growth for 12 Sprague-Dawley rats (six female, six male). Curved-reslicing was performed on μCT slices to generate 11 equidistant cross-sectional images that covered the middle 90 % of skull thickness and the entire length of the coronal suture. The suture linear interdigitation index (LII) and width were measured using a marching algorithm.
The average coronal suture LII increased by 15.3 % while the width decreased by 53.5 % at 21 weeks compared to 7 weeks of age, and repeated measures one-way analysis of variance with post-hoc multiple comparisons with Bonferroni adjustment revealed that these differences are statistically significant (p < 0.01). Linear mixed-effect models (LMM) were created for the prediction of rat coronal suture LII and width based on age, relative location through the skull thickness and initial morphometric measurements at the inner surface of the skull. When random effects are considered, the LMM was able to explain up to 97 % and 78 % of variations of suture LII and width, respectively. The presented study has established a novel curved-reslicing method to obtain quantitative 3D information surrounding cranial sutures and demonstrated strong predictive capabilities for suture morphometric changes with age. Future studies considering craniofacial sutures abnormalities will benefit from the presented work through novel methods of studying 3D quantitative morphometry.
{"title":"Three-dimensional cranial suture morphometric changes in young rats during normal growth","authors":"Tsolmonbaatar Khurelbaatar , Leah Fisher , Lindsey Westover , Michael R. Doschak , Dan L. Romanyk","doi":"10.1016/j.bone.2024.117336","DOIUrl":"10.1016/j.bone.2024.117336","url":null,"abstract":"<div><div>The age-based morphometric changes of cranial sutures are not well established, particularly in a quantitative manner. Most prior work utilized planar reslicing approaches to analyze sutures and the quantitative measurements of suture morphometry were limited to a short segment not following the true skull shape. The present study aimed to investigate the age-based morphometric changes of the coronal suture during normal growth of young rats using a novel curved-reslicing approach.</div><div>Longitudinal in vivo micro-computed tomography (μCT) scans were completed at five time points (7, 9, 11, 16 and 21 weeks of age) during normal growth for 12 Sprague-Dawley rats (six female, six male). Curved-reslicing was performed on μCT slices to generate 11 equidistant cross-sectional images that covered the middle 90 % of skull thickness and the entire length of the coronal suture. The suture linear interdigitation index (LII) and width were measured using a marching algorithm.</div><div>The average coronal suture LII increased by 15.3 % while the width decreased by 53.5 % at 21 weeks compared to 7 weeks of age, and repeated measures one-way analysis of variance with post-hoc multiple comparisons with Bonferroni adjustment revealed that these differences are statistically significant (<em>p</em> < 0.01). Linear mixed-effect models (LMM) were created for the prediction of rat coronal suture LII and width based on age, relative location through the skull thickness and initial morphometric measurements at the inner surface of the skull. When random effects are considered, the LMM was able to explain up to 97 % and 78 % of variations of suture LII and width, respectively. The presented study has established a novel curved-reslicing method to obtain quantitative 3D information surrounding cranial sutures and demonstrated strong predictive capabilities for suture morphometric changes with age. Future studies considering craniofacial sutures abnormalities will benefit from the presented work through novel methods of studying 3D quantitative morphometry.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"191 ","pages":"Article 117336"},"PeriodicalIF":3.5,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hajdu Cheney Syndrome (HCS), a monogenic disorder associated with NOTCH2 pathogenic variants, presents with neurological, craniofacial and skeletal abnormalities. Mouse models of the disease exhibit osteopenia. To determine the consequences of a HCS pathogenic variant in human cells, induced pluripotent NCRM1 and NCRM5 stem (iPS) cells harboring a NOTCH26949C>T mutation or null for HES1 alleles were created. Parental iPSCs, NOTCH26949C>T, HES1 null and control cells, free of chromosomal aberrations were cultured under conditions of neural crest, mesenchymal and osteogenic cell differentiation, or of embryoid body, hematopoietic and osteoclast cell differentiation. The expected cell phenotype was confirmed by cell surface markers and gene signature. NOTCH26949C>T cells displayed enhanced expression of Notch target genes demonstrating the presence of a NOTCH2 gain-of-function. There was a modest enhancement of osteogenesis in NOTCH26949C>T cells manifested by increased mineralized nodule formation and SP7, ALPL and BGLAP mRNA expression. There was enhanced osteoclastogenesis in NOTCH26949C>T cells as evidenced by increased number of osteoclasts and a transient increase in ACP5, CALCR and CTSK transcripts. Osteoblastogenesis was minimally affected by the HES1 deletion, but osteoclast differentiation was significantly impaired. In conclusion, a NOTCH2 pathogenic variant causes modest increases in osteoblastogenesis and osteoclastogenesis and HES1 is required for osteoclast differentiation in human iPS cells in vitro.
{"title":"A NOTCH2 pathogenic variant and HES1 regulate osteoclastogenesis in induced pluripotent stem cells","authors":"Ernesto Canalis , Lauren Schilling , Emily Denker , Christopher Stoddard , Jungeun Yu","doi":"10.1016/j.bone.2024.117334","DOIUrl":"10.1016/j.bone.2024.117334","url":null,"abstract":"<div><div>Hajdu Cheney Syndrome (HCS), a monogenic disorder associated with <em>NOTCH2</em> pathogenic variants, presents with neurological, craniofacial and skeletal abnormalities. Mouse models of the disease exhibit osteopenia. To determine the consequences of a HCS pathogenic variant in human cells, induced pluripotent NCRM1 and NCRM5 stem (iPS) cells harboring a <em>NOTCH2</em><sup><em>6949C>T</em></sup> mutation or null for <em>HES1</em> alleles were created. Parental iPSCs, <em>NOTCH2</em><sup><em>6949C>T</em></sup>, <em>HES1</em> null and control cells, free of chromosomal aberrations were cultured under conditions of neural crest, mesenchymal and osteogenic cell differentiation, or of embryoid body, hematopoietic and osteoclast cell differentiation. The expected cell phenotype was confirmed by cell surface markers and gene signature. <em>NOTCH2</em><sup><em>6949C>T</em></sup> cells displayed enhanced expression of Notch target genes demonstrating the presence of a NOTCH2 gain-of-function. There was a modest enhancement of osteogenesis in <em>NOTCH2</em><sup><em>6949C>T</em></sup> cells manifested by increased mineralized nodule formation and <em>SP7</em>, <em>ALPL</em> and <em>BGLAP</em> mRNA expression. There was enhanced osteoclastogenesis in <em>NOTCH2</em><sup><em>6949C>T</em></sup> cells as evidenced by increased number of osteoclasts and a transient increase in <em>ACP5</em>, <em>CALCR</em> and <em>CTSK</em> transcripts. Osteoblastogenesis was minimally affected by the <em>HES1</em> deletion, but osteoclast differentiation was significantly impaired. In conclusion, a <em>NOTCH2</em> pathogenic variant causes modest increases in osteoblastogenesis and osteoclastogenesis and HES1 is required for osteoclast differentiation in human iPS cells <em>in vitro</em>.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"191 ","pages":"Article 117334"},"PeriodicalIF":3.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142690081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-19DOI: 10.1016/j.bone.2024.117333
Ziyi Wang , Zhenyuan Gao , Yi-fei Yang , Bi Liu , Fei Yu , Hai-ming Ye , Ming Lei , Xiaoming Wu
Background
Osteosarcoma, as the most common primary malignant bone tumor, has become one of the main causes of cancer-related deaths in adolescents and children. This study thus proposes new biomarkers for OS based on whole-transcriptome re-analysis and experimental confirmation.
Methods
We find two circRNA dataset related to OS, from tissue and cell perspectives respectively, from the GEO database. Analysis of the tumor group and control group data used GEO2R, to obtain the differentially expressed (DE) circRNAs and take the intersection. The downstream miRNAs were predicted and subsequently the targeted mRNAs for these miRNAs were collected. These targeted mRNAs intersected with prognostic mRNAs reported in previous literature. CircRNA/miRNA/mRNA and circRNA/miRNA/mRNA/key pathway networks were constructed and GO and KEGG analyses were done. The prognostic values of hsa_circ_0032462, miR-488-3p, and SLC7A were confirmed in OS using Kaplan-Meier analyses and univariate/multivariate analyses. And the cellular functions of these three factors in OS were further explored through cell experiments.
Results
Five DEcircRNAs were obtained, targeting 42 miRNAs and linking 67 prognostic-related mRNA. GO analysis and KEGG analysis indicate that the mRNAs in the network were involved in various biological processes and signaling pathways related to OS. The luciferase report validated the targeting relationship of hsa_circ_0032462, miR-488-3p, and SLC7A. Cell survival, migration, and invasion experiments found that hsa_circ_0032462 and SLC7A promoted OS, while miR-488-3p inhibited OS.
Conclusion
Aberrantly expressed circRNAs in OS are involved in OS progression via the ceRNA network. Hsa_circ_0032462-miR-488-3p-SLC7A1 axis can be developed to be alternative therapeutic targets for OS.
{"title":"The functions and clinical implications of hsa_circ_0032462-miR-488-3p-SLC7A1 axis in human osteosarcoma","authors":"Ziyi Wang , Zhenyuan Gao , Yi-fei Yang , Bi Liu , Fei Yu , Hai-ming Ye , Ming Lei , Xiaoming Wu","doi":"10.1016/j.bone.2024.117333","DOIUrl":"10.1016/j.bone.2024.117333","url":null,"abstract":"<div><h3>Background</h3><div>Osteosarcoma, as the most common primary malignant bone tumor, has become one of the main causes of cancer-related deaths in adolescents and children. This study thus proposes new biomarkers for OS based on whole-transcriptome re-analysis and experimental confirmation.</div></div><div><h3>Methods</h3><div>We find two circRNA dataset related to OS, from tissue and cell perspectives respectively, from the GEO database. Analysis of the tumor group and control group data used GEO2R, to obtain the differentially expressed (DE) circRNAs and take the intersection. The downstream miRNAs were predicted and subsequently the targeted mRNAs for these miRNAs were collected. These targeted mRNAs intersected with prognostic mRNAs reported in previous literature. CircRNA/miRNA/mRNA and circRNA/miRNA/mRNA/key pathway networks were constructed and GO and KEGG analyses were done. The prognostic values of hsa_circ_0032462, miR-488-3p, and SLC7A were confirmed in OS using Kaplan-Meier analyses and univariate/multivariate analyses. And the cellular functions of these three factors in OS were further explored through cell experiments.</div></div><div><h3>Results</h3><div>Five DEcircRNAs were obtained, targeting 42 miRNAs and linking 67 prognostic-related mRNA. GO analysis and KEGG analysis indicate that the mRNAs in the network were involved in various biological processes and signaling pathways related to OS. The luciferase report validated the targeting relationship of hsa_circ_0032462, miR-488-3p, and SLC7A. Cell survival, migration, and invasion experiments found that hsa_circ_0032462 and SLC7A promoted OS, while miR-488-3p inhibited OS.</div></div><div><h3>Conclusion</h3><div>Aberrantly expressed circRNAs in OS are involved in OS progression via the ceRNA network. Hsa_circ_0032462-miR-488-3p-SLC7A1 axis can be developed to be alternative therapeutic targets for OS.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"191 ","pages":"Article 117333"},"PeriodicalIF":3.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142683871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-17DOI: 10.1016/j.bone.2024.117335
Hyerim Park , S. Anand Narayanan , Jacob T. Caldwell , Bradley J. Behnke , Judy M. Muller-Delp , Michael D. Delp
Aging leads to progressive bone loss, which is associated with impaired bone and marrow perfusion. The purpose of this study was to determine whether chronic exercise training enhances blood flow to the femur at rest and during exercise, and elucidate whether putative changes in training-induced bone perfusion are associated with alterations in the intrinsic vasomotor properties of the femoral principal nutrient artery (PNA) in old age.
Young (4–6 mo old) and old (20–22 mo old) male Fischer-344 rats were either treadmill exercise trained (ET) or remained sedentary (SED). Regional blood flow to the femur was assessed at rest and during treadmill exercise. Endothelium-dependent (acetylcholine, ACh) and -independent (Dea-NONOate) vasodilator, and vasoconstrictor (phenylephrine (PE), KCl and myogenic) responses of femoral PNAs were determined.
Exercise training led to higher blood flow to distal metaphysis and epiphysis in old rats at rest, and old ET rats showed greater regional blood flow during exercise compared to old SED rats. The increased blood flow to the proximal and distal metaphysis and epiphysis were also higher in old ET rats than that in young ET rats. Exercise training enhanced the vasodilator response to ACh, corresponding to increased eNOS expression in femoral PNAs from both young and old rats. Aging did not alter PE- or KCl-induced vasoconstriction, whereas myogenic responses were impaired. Exercise training enhanced vasoconstrictor responses to PE in old rats but had no effect on KCl or myogenic responses in either group.
These data demonstrate that exercise training enhances both regional bone and marrow blood flow and vasodilator responses, which are impaired in the femora of old SED rats.
衰老会导致渐进性骨质流失，这与骨和骨髓灌注受损有关。本研究的目的是确定慢性运动训练是否能增强静息时和运动时股骨的血流量，并阐明训练诱导的骨灌注的假定变化是否与老年股骨主要营养动脉（PNA）内在血管运动特性的改变有关。对年轻（4-6 个月大）和年老（20-22 个月大）的雄性 Fischer-344 大鼠进行跑步机运动训练（ET）或保持静坐（SED）。对大鼠休息时和跑步机运动时股骨的区域血流量进行评估。测定了股骨 PNA 的内皮依赖性（乙酰胆碱，ACh）和非依赖性（壬酸去甲肾上腺素）血管舒张和血管收缩（苯肾上腺素（PE）、氯化钾和肌源性）反应。运动训练使老龄大鼠静止时远端骨骺和骨骺的血流量增加，与老龄SED大鼠相比，老龄ET大鼠在运动时显示出更大的区域血流量。与年轻 ET 大鼠相比，老年 ET 大鼠干骺端和干骺端的血流量也更高。运动训练增强了血管对 ACh 的扩张反应，这与年轻和年老大鼠股骨 PNA 中 eNOS 表达的增加相对应。衰老不会改变 PE 或 KCl 诱导的血管收缩，而肌源性反应则会受损。运动训练增强了老年大鼠对 PE 的血管收缩反应，但对两组大鼠的 KCl 或肌生成反应均无影响。这些数据表明，运动训练可增强老龄 SED 大鼠股骨中受损的区域骨和骨髓血流以及血管扩张反应。
{"title":"Effects of aging and exercise training on bone and marrow blood flow and vascular function","authors":"Hyerim Park , S. Anand Narayanan , Jacob T. Caldwell , Bradley J. Behnke , Judy M. Muller-Delp , Michael D. Delp","doi":"10.1016/j.bone.2024.117335","DOIUrl":"10.1016/j.bone.2024.117335","url":null,"abstract":"<div><div>Aging leads to progressive bone loss, which is associated with impaired bone and marrow perfusion. The purpose of this study was to determine whether chronic exercise training enhances blood flow to the femur at rest and during exercise, and elucidate whether putative changes in training-induced bone perfusion are associated with alterations in the intrinsic vasomotor properties of the femoral principal nutrient artery (PNA) in old age.</div><div>Young (4–6 mo old) and old (20–22 mo old) male Fischer-344 rats were either treadmill exercise trained (ET) or remained sedentary (SED). Regional blood flow to the femur was assessed at rest and during treadmill exercise. Endothelium-dependent (acetylcholine, ACh) and -independent (Dea-NONOate) vasodilator, and vasoconstrictor (phenylephrine (PE), KCl and myogenic) responses of femoral PNAs were determined.</div><div>Exercise training led to higher blood flow to distal metaphysis and epiphysis in old rats at rest, and old ET rats showed greater regional blood flow during exercise compared to old SED rats. The increased blood flow to the proximal and distal metaphysis and epiphysis were also higher in old ET rats than that in young ET rats. Exercise training enhanced the vasodilator response to ACh, corresponding to increased eNOS expression in femoral PNAs from both young and old rats. Aging did not alter PE- or KCl-induced vasoconstriction, whereas myogenic responses were impaired. Exercise training enhanced vasoconstrictor responses to PE in old rats but had no effect on KCl or myogenic responses in either group.</div><div>These data demonstrate that exercise training enhances both regional bone and marrow blood flow and vasodilator responses, which are impaired in the femora of old SED rats.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"192 ","pages":"Article 117335"},"PeriodicalIF":3.5,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142677737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-17DOI: 10.1016/j.bone.2024.117332
Yunfa Wang , Bofan Chen , Xinyue Liu , Haimin Zeng , Bin Chen , Zhilin Wang , Qingpiao Yang , Jie Peng , Liang Hao
Background
Musculoskeletal (MSK) diseases represent a significant global public health challenge. Conducting comprehensive research on MSK diseases in China holds profound implications for public health.
Methods
This study utilized data from the Global Burden of Disease 2021 (GBD 2021) to analyze the incidence rate, prevalence rate, mortality rate, disability-adjusted life years (DALYs), years lived with disability (YLDs), and years of life lost (YLLs) of MSK diseases in China from 1990 to 2021. Trends were evaluated using annual percentage change (APC), average annual percentage change (AAPC), and estimated annual percentage change (EAPC). Future disease trends were predicted using the Bayesian Age-Period-Cohort (BAPC) model.
Results
China had the highest number of DALYs cases globally, totaling 30.4194 million. Low back pain (LBP) represented the largest burden, while hand osteoarthritis exhibited the fastest growth. Differences in disease burden were observed across various genders and age groups. Predictions indicate that between 2021 and 2030, the age-standardized DALYs rate in China will increase annually, reaching 1779.08 per 100,000 population by 2030. Environmental (occupational) factors had the most significant impact on the age-standardized DALYs rate, whereas renal dysfunction had the least impact. The SDI showed a moderately strong positive correlation with the age-standardized DALYs rate of MSK diseases.
Conclusion
Over the past 20 years, the prevalence of MSK diseases in China has experienced a slight increase, while other epidemiological burden indicators have shown a downward trend. Projections indicate that the overall disease burden of MSK in China will continue to rise over the next decade, underscoring the need for early intervention strategies. Moreover, substantial differences in MSK disease burden across genders and age groups highlight the importance of developing targeted policy interventions to mitigate this burden.
{"title":"Temporal trends in the burden of musculoskeletal diseases in China from 1990 to 2021 and predictions for 2021 to 2030","authors":"Yunfa Wang , Bofan Chen , Xinyue Liu , Haimin Zeng , Bin Chen , Zhilin Wang , Qingpiao Yang , Jie Peng , Liang Hao","doi":"10.1016/j.bone.2024.117332","DOIUrl":"10.1016/j.bone.2024.117332","url":null,"abstract":"<div><h3>Background</h3><div>Musculoskeletal (MSK) diseases represent a significant global public health challenge. Conducting comprehensive research on MSK diseases in China holds profound implications for public health.</div></div><div><h3>Methods</h3><div>This study utilized data from the Global Burden of Disease 2021 (GBD 2021) to analyze the incidence rate, prevalence rate, mortality rate, disability-adjusted life years (DALYs), years lived with disability (YLDs), and years of life lost (YLLs) of MSK diseases in China from 1990 to 2021. Trends were evaluated using annual percentage change (APC), average annual percentage change (AAPC), and estimated annual percentage change (EAPC). Future disease trends were predicted using the Bayesian Age-Period-Cohort (BAPC) model.</div></div><div><h3>Results</h3><div>China had the highest number of DALYs cases globally, totaling 30.4194 million. Low back pain (LBP) represented the largest burden, while hand osteoarthritis exhibited the fastest growth. Differences in disease burden were observed across various genders and age groups. Predictions indicate that between 2021 and 2030, the age-standardized DALYs rate in China will increase annually, reaching 1779.08 per 100,000 population by 2030. Environmental (occupational) factors had the most significant impact on the age-standardized DALYs rate, whereas renal dysfunction had the least impact. The SDI showed a moderately strong positive correlation with the age-standardized DALYs rate of MSK diseases.</div></div><div><h3>Conclusion</h3><div>Over the past 20 years, the prevalence of MSK diseases in China has experienced a slight increase, while other epidemiological burden indicators have shown a downward trend. Projections indicate that the overall disease burden of MSK in China will continue to rise over the next decade, underscoring the need for early intervention strategies. Moreover, substantial differences in MSK disease burden across genders and age groups highlight the importance of developing targeted policy interventions to mitigate this burden.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"191 ","pages":"Article 117332"},"PeriodicalIF":3.5,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142650036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-15DOI: 10.1016/j.bone.2024.117331
Ping Li , Wensheng Zhang , Jie Zhang , Jie Liu , Jiaming Fu , Zhengnong Wei , Shiyong Le , Jiajia Xu , Liang Wang , Zhongmin Zhang
Background
Heterotopic ossification (HO) refers to the development of bone tissue in areas other than the skeletal system. The development and maturation of the skeletal system are significantly influenced by macrophage migration inhibitory factor (MIF). The objective of this study was to examine the impact of MIF on the in vitro osteogenic differentiation and mineralization of tendon-derived stem cells (TDSCs), mediated by a positive feedback loop involving ROS/HIF-1α/MIF.
Methods
TDSCs were isolated and identified from the hind limbs of C57/BL6 mice. The functional and procedural roles of MIF in HO, focusing on the impact of MIF on the differentiation of TDSCs into bone-forming cells were investigated in vitro. Seventy-five mice were randomly assigned to five groups. Gene expression and histological analyses of MIF and its receptors, and determine the expression of osteogenic markers in vivo.
Results
The results revealed a positive and concentration-dependent effect of MIF on the osteogenic differentiation of TDSCs. Furthermore, an ROS/HIF-1α/MIF positive loop was detected in the simulated early trauma hypoxic microenvironment, resulting in a 3 to 4 folds increase in MIF expression levels. MIF was also found to enhance double the expression levels of markers associated with bone and cartilage at the site of injury, consequently facilitating the development of HO, which was thought to be associated with the activation of the Wnt/β-catenin pathway.
Conclusion
MIF, which mediates the ROS/HIF-1α/MIF positive feedback loop during the hypoxic phase of HO, triggers the Wnt/β-catenin signaling pathway to enhance the osteogenic differentiation and formation of HO in TDSCs.
{"title":"Macrophage migration inhibitory factor promotes heterotopic ossification by mediating ROS/HIF-1α positive feedback loop and activating Wnt/β-catenin signaling pathway","authors":"Ping Li , Wensheng Zhang , Jie Zhang , Jie Liu , Jiaming Fu , Zhengnong Wei , Shiyong Le , Jiajia Xu , Liang Wang , Zhongmin Zhang","doi":"10.1016/j.bone.2024.117331","DOIUrl":"10.1016/j.bone.2024.117331","url":null,"abstract":"<div><h3>Background</h3><div>Heterotopic ossification (HO) refers to the development of bone tissue in areas other than the skeletal system. The development and maturation of the skeletal system are significantly influenced by macrophage migration inhibitory factor (MIF). The objective of this study was to examine the impact of MIF on the in vitro osteogenic differentiation and mineralization of tendon-derived stem cells (TDSCs), mediated by a positive feedback loop involving ROS/HIF-1α/MIF.</div></div><div><h3>Methods</h3><div>TDSCs were isolated and identified from the hind limbs of C57/BL6 mice. The functional and procedural roles of MIF in HO, focusing on the impact of MIF on the differentiation of TDSCs into bone-forming cells were investigated in vitro. Seventy-five mice were randomly assigned to five groups. Gene expression and histological analyses of MIF and its receptors, and determine the expression of osteogenic markers in vivo.</div></div><div><h3>Results</h3><div>The results revealed a positive and concentration-dependent effect of MIF on the osteogenic differentiation of TDSCs. Furthermore, an ROS/HIF-1α/MIF positive loop was detected in the simulated early trauma hypoxic microenvironment, resulting in a 3 to 4 folds increase in MIF expression levels. MIF was also found to enhance double the expression levels of markers associated with bone and cartilage at the site of injury, consequently facilitating the development of HO, which was thought to be associated with the activation of the Wnt/β-catenin pathway.</div></div><div><h3>Conclusion</h3><div>MIF, which mediates the ROS/HIF-1α/MIF positive feedback loop during the hypoxic phase of HO, triggers the Wnt/β-catenin signaling pathway to enhance the osteogenic differentiation and formation of HO in TDSCs.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"190 ","pages":"Article 117331"},"PeriodicalIF":3.5,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142645329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-14DOI: 10.1016/j.bone.2024.117328
Toru Hiraga
Bone is a common and frequent site of metastasis in cancer patients, leading to a significant reduction in quality of life and increased mortality. Bone marrow, the primary site of hematopoiesis, also serves as both a primary and secondary lymphoid organ. It harbors and supports a diverse array of immune cells, thereby creating a distinct immune microenvironment. These immune cells engage in a range of activities, including anti-tumor, pro-tumor, or a combination of both, which influence the development and progression of bone metastases. Rapid advances in cancer immunotherapy have underscored its potential to eradicate bone metastases. However, clinical outcomes have not yet met expectations. To improve the efficacy of immunotherapy, it is crucial to gain a comprehensive and in-depth understanding of the immune microenvironment within bone metastases. This review provides an overview of the current understanding of the role of different immune cells, their anti-tumor and pro-tumor activities, and their overall contribution to bone metastasis.
{"title":"Immune microenvironment of cancer bone metastasis","authors":"Toru Hiraga","doi":"10.1016/j.bone.2024.117328","DOIUrl":"10.1016/j.bone.2024.117328","url":null,"abstract":"<div><div>Bone is a common and frequent site of metastasis in cancer patients, leading to a significant reduction in quality of life and increased mortality. Bone marrow, the primary site of hematopoiesis, also serves as both a primary and secondary lymphoid organ. It harbors and supports a diverse array of immune cells, thereby creating a distinct immune microenvironment. These immune cells engage in a range of activities, including anti-tumor, pro-tumor, or a combination of both, which influence the development and progression of bone metastases. Rapid advances in cancer immunotherapy have underscored its potential to eradicate bone metastases. However, clinical outcomes have not yet met expectations. To improve the efficacy of immunotherapy, it is crucial to gain a comprehensive and in-depth understanding of the immune microenvironment within bone metastases. This review provides an overview of the current understanding of the role of different immune cells, their anti-tumor and pro-tumor activities, and their overall contribution to bone metastasis.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"191 ","pages":"Article 117328"},"PeriodicalIF":3.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142645327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-14DOI: 10.1016/j.bone.2024.117330
Qianyi Qiu , Junzhang Huang , Yi Yang , Yinxia Zhao , Xiongfeng Zhu , Jiayou Peng , Cuiling Zhu , Shuxue Liu , Weiqing Peng , Junqi Sun , Xinru Zhang , MianWen Li , Xintao Zhang , Jiaping Hu , Qingling Xie , Qianjin Feng , Xiaodong Zhang
Vertebral compression fractures (VCFs) are the most common type of osteoporotic fractures, yet they are often clinically silent and undiagnosed. Chest frontal radiographs (CFRs) are frequently used in clinical practice and a portion of VCFs can be detected through this technology. This study aimed to develop an automatic artificial intelligence (AI) tool using deep learning (DL) model for the opportunistic screening of VCFs from CFRs. The datasets were collected from four medical centers, comprising 19,145 vertebrae (T6-T12) from 2735 patients. Patients from Center 1, 2 and 3 were divided into the training and internal testing datasets in an 8:2 ratio (n = 2361, with 16,527 vertebrae). Patients from Center 4 were used as the external test dataset (n = 374, with 2618 vertebrae). Model performance was assessed using sensitivity, specificity, accuracy and the area under the curve (AUC). A reader study with five clinicians of different experience levels was conducted with and without AI assistance. In the internal testing dataset, the model achieved a sensitivity of 83.0 % and an AUC of 0.930 at the fracture level. In the external testing dataset, the model demonstrated a sensitivity of 78.4 % and an AUC of 0.942 at the fracture level. The model's sensitivity outperformed that of five clinicians with different levels of experience. Notably, AI assistance significantly improved sensitivity at the patient level for both junior clinicians (from 56.1 % without AI to 81.6 % with AI) and senior clinicians (from 65.0 % to 85.6 %). In conclusion, the automatic AI tool significantly increases clinicians' sensitivity in diagnosing fractures on CFRs, showing great potential for the opportunistic screening of VCFs.
{"title":"Automatic AI tool for opportunistic screening of vertebral compression fractures on chest frontal radiographs: A multicenter study","authors":"Qianyi Qiu , Junzhang Huang , Yi Yang , Yinxia Zhao , Xiongfeng Zhu , Jiayou Peng , Cuiling Zhu , Shuxue Liu , Weiqing Peng , Junqi Sun , Xinru Zhang , MianWen Li , Xintao Zhang , Jiaping Hu , Qingling Xie , Qianjin Feng , Xiaodong Zhang","doi":"10.1016/j.bone.2024.117330","DOIUrl":"10.1016/j.bone.2024.117330","url":null,"abstract":"<div><div>Vertebral compression fractures (VCFs) are the most common type of osteoporotic fractures, yet they are often clinically silent and undiagnosed. Chest frontal radiographs (CFRs) are frequently used in clinical practice and a portion of VCFs can be detected through this technology. This study aimed to develop an automatic artificial intelligence (AI) tool using deep learning (DL) model for the opportunistic screening of VCFs from CFRs. The datasets were collected from four medical centers, comprising 19,145 vertebrae (T6-T12) from 2735 patients. Patients from Center 1, 2 and 3 were divided into the training and internal testing datasets in an 8:2 ratio (<em>n</em> = 2361, with 16,527 vertebrae). Patients from Center 4 were used as the external test dataset (<em>n</em> = 374, with 2618 vertebrae). Model performance was assessed using sensitivity, specificity, accuracy and the area under the curve (AUC). A reader study with five clinicians of different experience levels was conducted with and without AI assistance. In the internal testing dataset, the model achieved a sensitivity of 83.0 % and an AUC of 0.930 at the fracture level. In the external testing dataset, the model demonstrated a sensitivity of 78.4 % and an AUC of 0.942 at the fracture level. The model's sensitivity outperformed that of five clinicians with different levels of experience. Notably, AI assistance significantly improved sensitivity at the patient level for both junior clinicians (from 56.1 % without AI to 81.6 % with AI) and senior clinicians (from 65.0 % to 85.6 %). In conclusion, the automatic AI tool significantly increases clinicians' sensitivity in diagnosing fractures on CFRs, showing great potential for the opportunistic screening of VCFs.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"191 ","pages":"Article 117330"},"PeriodicalIF":3.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142645325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-09DOI: 10.1016/j.bone.2024.117326
Linyi Liu , Phuong T. Le , Victoria E. DeMambro , Tiange Feng , Hanghang Liu , Wangyang Ying , Roland Baron , Clifford J. Rosen
Caloric restriction (CR), commonly used as both a lifestyle choice and medical strategy, has been shown to adversely impact appendicular bone mass. However, its influence on alveolar bone health and the underlying mechanisms remain poorly understood. In this study, 8-week-old C57BL/6 J mice were fed with 30 % CR for 8 weeks. Micro-architecture, histologic parameters, and in vitro trajectories of osteoblast and adipocyte differentiation were examined. To further explore the underlying mechanisms, metabolic cages and in vitro bioenergetics were performed. Our results showed that 8 weeks of CR led to trabecular and cortical bone loss in the mandibles of female mice. CR in female mice decreased bone formation and bone resorption activities but induced adiposity in the mandibles. After CR, the adipogenesis in mesenchymal cells from orofacial bones (OMSCs) was greatly accelerated, whereas osteogenic differentiation was reduced in females. Undifferentiated CR OMSCs showed marked suppression in ATP production rates from mitochondria in female mice. ATP production rates decreased after osteogenesis but were upregulated during adipogenesis in female mice. Conversely, the generation of reactive oxygen species (ROS) was heightened during both osteoblastic and adipogenic differentiation in female CR groups. Collectively, our study indicated that CR could cause significant bone loss in the mandibles of female mice, almost certainly related to a reduced ATP supply and the unregulated generation of ROS.
热量限制（CR）通常被用作一种生活方式选择和医疗策略，已被证明会对阑尾骨量产生不利影响。然而，人们对其对牙槽骨健康的影响及其内在机制仍知之甚少。在这项研究中，8 周大的 C57BL/6 J 小鼠连续 8 周喂食 30% 的 CR。研究人员对小鼠的微观结构、组织学参数以及成骨细胞和脂肪细胞的体外分化轨迹进行了检测。为进一步探究其潜在机制，还进行了代谢笼和体外生物能研究。我们的研究结果表明，8 周的 CR 会导致雌性小鼠下颌骨的骨小梁和皮质骨流失。雌性小鼠CR降低了骨形成和骨吸收活性，但诱导了下颌骨的脂肪生成。CR 后，雌性小鼠口面部骨骼间充质细胞（OMSCs）的脂肪生成大大加快，而成骨分化却减少了。未分化的 CR OMSCs 显示，雌性小鼠线粒体产生 ATP 的速率明显受到抑制。雌性小鼠在成骨后 ATP 生成率下降，但在脂肪生成过程中 ATP 生成率上升。相反，在雌性 CR 组的成骨和成脂分化过程中，活性氧（ROS）的生成都有所增加。总之，我们的研究表明，CR 可导致雌性小鼠下颌骨骨质大量流失，这几乎可以肯定与 ATP 供应减少和 ROS 生成失调有关。
{"title":"Calorie restriction induces mandible bone loss by regulating mitochondrial function","authors":"Linyi Liu , Phuong T. Le , Victoria E. DeMambro , Tiange Feng , Hanghang Liu , Wangyang Ying , Roland Baron , Clifford J. Rosen","doi":"10.1016/j.bone.2024.117326","DOIUrl":"10.1016/j.bone.2024.117326","url":null,"abstract":"<div><div>Caloric restriction (CR), commonly used as both a lifestyle choice and medical strategy, has been shown to adversely impact appendicular bone mass. However, its influence on alveolar bone health and the underlying mechanisms remain poorly understood. In this study, 8-week-old C57BL/6 J mice were fed with 30 % CR for 8 weeks. Micro-architecture, histologic parameters, and in vitro trajectories of osteoblast and adipocyte differentiation were examined. To further explore the underlying mechanisms, metabolic cages and in vitro bioenergetics were performed. Our results showed that 8 weeks of CR led to trabecular and cortical bone loss in the mandibles of female mice. CR in female mice decreased bone formation and bone resorption activities but induced adiposity in the mandibles. After CR, the adipogenesis in mesenchymal cells from orofacial bones (OMSCs) was greatly accelerated, whereas osteogenic differentiation was reduced in females. Undifferentiated CR OMSCs showed marked suppression in ATP production rates from mitochondria in female mice. ATP production rates decreased after osteogenesis but were upregulated during adipogenesis in female mice. Conversely, the generation of reactive oxygen species (ROS) was heightened during both osteoblastic and adipogenic differentiation in female CR groups. Collectively, our study indicated that CR could cause significant bone loss in the mandibles of female mice, almost certainly related to a reduced ATP supply and the unregulated generation of ROS.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"190 ","pages":"Article 117326"},"PeriodicalIF":3.5,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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