Bone最新文献 - Book学术

Beyond BMD: Clinical implications of vertebral biomechanical decline under ADT

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2025-03-31 DOI: 10.1016/j.bone.2025.117476

Shengyi Chen , Yuekun Fang , Bin Cheng

引用次数: 0

Serum bicarbonate concentration is associated with bone density in adults with type 2 diabetes mellitus: African American-Diabetes Heart Study

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2025-03-27 DOI: 10.1016/j.bone.2025.117470

Minesh Khatri , Kishan Rao , Meredith Akerman , Jean Ancion , Barry I. Freedman , Jasmin Divers

Background

Osteoporosis is a significant cause of morbidity and mortality in the aging population. Individuals with type 2 diabetes mellitus (T2D) typically have higher bone density yet also a higher rate of fractures. Blacks, meanwhile, have a lower incidence of osteoporosis compared to European Americans. Serum bicarbonate may be a risk factor for bone loss, but studies are conflicting, and little is known about this relationship in T2D or Blacks.

Methods

We examined the longitudinal relationship between serum bicarbonate and change in bone density in 300 participants with T2D in the African American-Diabetes Heart Study (AA-DHS). Serum bicarbonate was measured at baseline, and bone density was assessed using CT volumetric bone mineral density (vBMD) scans of the thoracic and lumbar vertebrae at baseline and after five years of follow-up. Multivariate linear regression models assessed associations between baseline serum bicarbonate and longitudinal change in vBMD, adjusted for multiple confounders.

Results

The cohort was 50 % female, with mean age and T2D duration 55.1 years and 10.2 years, respectively. The mean baseline serum bicarbonate was 26.6 (SD 3.3) mEq/L; median baseline lumbar spine vBMD 179.3 (IQR 148.2, 208.9) mg/cm³, and median baseline thoracic spine vBMD 204.9 (IQR 171.6, 231.9) mg/cm³. In fully-adjusted analyses, each 1 mEq/L increase in baseline serum bicarbonate was significantly associated with 5-year relative increase in lumbar vBMD (0.94 mg/cm³, p < 0.001) and thoracic vBMD (1.35 mg/cm³, p < 0.001), without a clear threshold effect or differences by sex.

Conclusions

In this cohort of Blacks with T2D, higher baseline serum bicarbonate levels were associated with improved changes in bone density over time. Further studies are needed to determine if alkali supplementation would ameliorate loss of bone density in this population.

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引用次数: 0

Visualization and quantification of RANK-RANKL binding for application to disease investigations and drug discovery

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2025-03-25 DOI: 10.1016/j.bone.2025.117473

Ken-ichi Nakahama , Shiho Hidaka , Kanako Goto , Mayu Tada , Tomoya Doi , Hiroyuki Nakamura , Masako Akiyama , Masahiro Shinohara

Receptor activator of NFκB (RANK)-receptor activator of NFκB ligand (RANKL) binding triggers the differentiation of osteoclasts, bone-resorbing cells. The imbalance between bone resorption by osteoclasts and bone formation by osteoblasts causes bone diseases. We herein report the real-time detection of RANK-RANKL binding using the NanoLuc method. Large-BiT-RANK and RANKL-Small-BiT fusion proteins were expressed in HeLa cells, and their co-culture exhibited chemiluminescence in the presence of luciferase substrates. This luminescence was inhibited by the treatment of cells with an anti-RANKL neutralization antibody, indicating that luminescence is dependent on RANK-RANKL binding. Moreover, mutations in RANKL (M198K or G278R) and RANK (G54R or K171G), based on mutations in autosomal recessive osteopetrosis (ARO) patients, did not exhibit the luminescence in the presence of their wild-type counterparts. HeLa cells expressing RANKL mutants did not support osteoclastogenesis. These results clearly indicate that the loss of binding by RANK-RANKL mutants is responsible for osteoclast-poor osteopetrosis in ARO patients. A nuclear factor kappa B reporter gene assay showed the impaired signal transduction of RANK (G54R) by RANKL. Therefore, our method successfully detected and quantified RANK-RANKL binding in living cells. Furthermore, our method is not only useful for investigating the mechanisms underlying osteoclast-poor ARO, but also for the screening of lead compounds that inhibit RANK-RANKL binding in osteoporosis patients. We identified a new compound with a three-dimensional structure that inhibits RANK-RANKL binding using our method. Our detection system for RANK-RANKL binding will contribute to both the development of anti-osteopetrosis drugs and a more detailed understanding of bone cell biology.

{"title":"Visualization and quantification of RANK-RANKL binding for application to disease investigations and drug discovery","authors":"Ken-ichi Nakahama , Shiho Hidaka , Kanako Goto , Mayu Tada , Tomoya Doi , Hiroyuki Nakamura , Masako Akiyama , Masahiro Shinohara","doi":"10.1016/j.bone.2025.117473","DOIUrl":"10.1016/j.bone.2025.117473","url":null,"abstract":"<div><div>Receptor activator of NFκB (RANK)-receptor activator of NFκB ligand (RANKL) binding triggers the differentiation of osteoclasts, bone-resorbing cells. The imbalance between bone resorption by osteoclasts and bone formation by osteoblasts causes bone diseases. We herein report the real-time detection of RANK-RANKL binding using the NanoLuc method. Large-BiT-RANK and RANKL-Small-BiT fusion proteins were expressed in HeLa cells, and their co-culture exhibited chemiluminescence in the presence of luciferase substrates. This luminescence was inhibited by the treatment of cells with an anti-RANKL neutralization antibody, indicating that luminescence is dependent on RANK-RANKL binding. Moreover, mutations in RANKL (M198K or G278R) and RANK (G54R or K171G), based on mutations in autosomal recessive osteopetrosis (ARO) patients, did not exhibit the luminescence in the presence of their wild-type counterparts. HeLa cells expressing RANKL mutants did not support osteoclastogenesis. These results clearly indicate that the loss of binding by RANK-RANKL mutants is responsible for osteoclast-poor osteopetrosis in ARO patients. A nuclear factor kappa B reporter gene assay showed the impaired signal transduction of RANK (G54R) by RANKL. Therefore, our method successfully detected and quantified RANK-RANKL binding in living cells. Furthermore, our method is not only useful for investigating the mechanisms underlying osteoclast-poor ARO, but also for the screening of lead compounds that inhibit RANK-RANKL binding in osteoporosis patients. We identified a new compound with a three-dimensional structure that inhibits RANK-RANKL binding using our method. Our detection system for RANK-RANKL binding will contribute to both the development of anti-osteopetrosis drugs and a more detailed understanding of bone cell biology.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"195 ","pages":"Article 117473"},"PeriodicalIF":3.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143726076","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}

引用次数: 0

A novel NEK1 variant disturbs the interaction between the C-terminal fragment of NEK1 and the VDAC1 channel, causing lethal short-rib polydactyly syndrome

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2025-03-25 DOI: 10.1016/j.bone.2025.117471

Karolina Gruca-Stryjak , Karolina Maciak , Maria Winiewska-Szajewska , Aneta Jurkiewicz , Monika Gora , Magdalena M. Kacprzak , Olga Drgas , Agnieszka Bialek-Proscinska , Agnieszka Sobczynska-Tomaszewska , Krzysztof D. Pluta , Aleksander Jamsheer , Wieslaw Markwitz , Jaroslaw Poznanski , Beata Burzynska

The NIMA-related kinase 1 (NEK1) gene belongs to the Never in Mitosis Gene A (NIMA) kinase family, a group whose members play essential roles in cell cycle regulation, specifically in cell division and ciliogenesis. Mutations in the NEK1 gene have been implicated in several diseases, including short-rib polydactyly syndrome (SRPS). SRPS is a bone growth disorder characterized by severe congenital anomalies. Here, we describe a family with a lethal form of SRPS due to a novel intronic variant in the NEK1 gene. Basing on whole-exome sequencing of fetuses with SRPS we identified a homozygous variant of the NEK1 gene at position c.3584-10T>A as the causative mutation. Bioinformatic methods and minigene splicing assays were then used to assess the harmfulness and functional impact of the variant. We found that the identified mutation leads to the synthesis of the NEK1 protein lacking 90C-terminal residues following the last coiled-coil region. Additional experiments were performed to identify proteins that interact with the C-terminal fragment of NEK1 absent in the mutated protein. We suggest that the interaction between the C-terminal fragment of NEK1 and the VDAC1 channel is essential for the VDAC1 phosphorylation, the absence of which is likely to affect ciliogenesis.

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引用次数: 0

Assessing bone mineral density and cortical geometry using high-resolution peripheral quantitative computed tomography in pediatric survivors of high-risk neuroblastoma with severe growth failure

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2025-03-24 DOI: 10.1016/j.bone.2025.117468

Sonia Gera , Michelle Guo , Yang Xie , Netanya Pollock , Minkeun Song , David R. Weber , Michelle Denburg , Babette Zemel , Sogol Mostoufi-Moab

Introduction

Survival of children with high-risk neuroblastoma (HR-NBL) has increased with multimodal therapy. cis-Retinoic acid (cis-RA), cornerstone of HR-NBL therapy, can cause osteoporosis and premature physeal closure. This study utilized high-resolution peripheral quantitative computed tomography (HR-pQCT), for 3D measures of volumetric bone mineral density (BMD) and microarchitecture, to assess impact of HR-NBL therapy on skeletal structure.

Methods

We prospectively enrolled 20 HR-NBL survivors and 20 age-, sex-, and race-matched healthy reference participants. We assessed leg lean mass adjusted for leg length by DXA and strength using a Biodex dynamometer. Tibia bone microarchitecture was assessed via HR-pQCT scans at 4 % of tibia length and a cortical site at 30 %. We compared tibia length (cm), cortical and trabecular vBMD (mg HA/cm³), geometric and structural parameters between groups. Linear regression models assessed group differences in bone microarchitecture adjusted for leg lean mass.

Results

Compared to reference participants, tibia length was significantly shorter in HR-NBL survivors (31.6 cm [27.7,39.5] vs. 36.1 cm [30.4,40], p < 0.005), consistent with significantly lower height Z-score in the HR-NBL cohort (p < 0.001). HR-NBL survivors demonstrated lower cortical area (178.3mm² [121.9273.5] vs. 214.6mm² [159.4326.9], p < 0.05) and cortical perimeter (60.0 mm [51.9,82.5] vs. 68.8 mm [57.7,90.8], p < 0.01). After adjusting for tibia length, these differences were no longer significant. Total, cortical, and trabecular volumetric BMD, were not significantly different between groups. Cortical geometry and peak torque deficits were associated with muscle deficits when adjusted for leg lean mass (p < 0.001).

Conclusion

Bone density was not severely impacted in HR-NBL survivors. Muscle deficits persisted years after treatment and underscored cortical geometry deficits.

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引用次数: 0

The GWAS candidate far upstream element binding protein 3 (FUBP3) is required for normal skeletal growth, and adult bone mass and strength in mice

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2025-03-24 DOI: 10.1016/j.bone.2025.117472

Laura M. Watts, Penny C. Sparkes, Hannah F. Dewhurst, Siobhan E. Guilfoyle, Andrea S. Pollard, Davide Komla-Ebri, Natalie C. Butterfield, Graham R. Williams, J.H. Duncan Bassett

Bone mineral density (BMD) and height are highly heritable traits for which hundreds of genetic loci have been linked through genome wide association studies (GWAS). FUBP3 is a DNA and RNA binding protein best characterised as a transcriptional regulator of c-Myc, but little is known about its role in vivo. Single nucleotide polymorphisms in FUBP3 at the 9q34.11 locus have been associated with BMD, fracture and height in multiple GWAS, but FUBP3 has no previously established role in the skeleton. We analysed Fubp3-deficient mice to determine the consequence of FUBP3 deficiency in vivo. Mice lacking Fubp3 had reduced survival to adulthood and impaired skeletal growth. Bone mass was decreased, most strikingly in the vertebrae, with altered trabecular micro-architecture. Fubp3 deficient bones were also weak. These data provide the first functional demonstration that Fubp3 is required for normal skeletal growth and development and maintenance of adult bone structure and strength, indicating that FUBP3 contributes to the GWAS association of 9q34.11 with variation in height, BMD and fracture.

{"title":"The GWAS candidate far upstream element binding protein 3 (FUBP3) is required for normal skeletal growth, and adult bone mass and strength in mice","authors":"Laura M. Watts, Penny C. Sparkes, Hannah F. Dewhurst, Siobhan E. Guilfoyle, Andrea S. Pollard, Davide Komla-Ebri, Natalie C. Butterfield, Graham R. Williams, J.H. Duncan Bassett","doi":"10.1016/j.bone.2025.117472","DOIUrl":"10.1016/j.bone.2025.117472","url":null,"abstract":"<div><div>Bone mineral density (BMD) and height are highly heritable traits for which hundreds of genetic loci have been linked through genome wide association studies (GWAS). FUBP3 is a DNA and RNA binding protein best characterised as a transcriptional regulator of <em>c-Myc</em>, but little is known about its role <em>in vivo</em>. Single nucleotide polymorphisms in <em>FUBP3</em> at the 9q34.11 locus have been associated with BMD, fracture and height in multiple GWAS, but FUBP3 has no previously established role in the skeleton. We analysed <em>Fubp3</em>-deficient mice to determine the consequence of FUBP3 deficiency <em>in vivo</em>. Mice lacking <em>Fubp3</em> had reduced survival to adulthood and impaired skeletal growth. Bone mass was decreased, most strikingly in the vertebrae, with altered trabecular micro-architecture. <em>Fubp3</em> deficient bones were also weak. These data provide the first functional demonstration that <em>Fubp3</em> is required for normal skeletal growth and development and maintenance of adult bone structure and strength, indicating that <em>FUBP3</em> contributes to the GWAS association of 9q34.11 with variation in height, BMD and fracture.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"195 ","pages":"Article 117472"},"PeriodicalIF":3.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143733698","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}

引用次数: 0

Dental and craniofacial manifestations in sponastrime dysplasia - An observational study

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2025-03-21 DOI: 10.1016/j.bone.2025.117469

Heidi Arponen , Helena Valta , Outi Mäkitie

Sponastrime dysplasia is an extremely rare autosomal recessive spondyloepimetaphyseal dysplasia characterized by short stature, midface hypoplasia, nasal alterations, and dental anomalies. This is, to date, the first comprehensive report on oral and craniofacial findings, and on subjective oral health-related quality of life as clinically and radiologically examined in two adults with sponastrime dysplasia.

Both subjects had typical features of sponastrime dysplasia with disproportionate short stature, hypertelorism and midface hypoplasia, and variants in the TONSL gene. One had a severe phenotype (adult height 91 cm), whereas the other exhibited moderate severity (adult height 135 cm). The notable variation in the disorder severity was also expressed in dental manifestations. Dentin dysplasia type I-like abnormalities were seen in tooth eruption and morphology. Dental roots were shortened in both individuals. The individual with severe growth failure had lost several permanent teeth and reported a moderate level of discomfort and impairment due to oral health issues, as evaluated with the Oral Health Impact Profile questionnaire. In contrast, the other individual had a full permanent dentition and minimal negative impact on oral health-related quality of life. Both had short jaw lengths and face height. The anteroposterior jaw relationships were normal. The jaws of the individual with a severe phenotype were retrognathic in relation to the skull base. Both had prominent forehead.

Due to significant craniofacial and dental involvement, individuals with sponastrime dysplasia should be regularly followed by a multidisciplinary medical team including a dentist, to maintain individuals' oral health and oral health-related quality of life.

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引用次数: 0

Extracellular pH is a critical regulator of osteoclast fusion, size and activation

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2025-03-20 DOI: 10.1016/j.bone.2025.117466

Bethan K. Davies , Andrew J. Skelton , Mark Hopkinson , Simon Lumb , Gill Holdsworth , Timothy R. Arnett , Isabel R. Orriss

Osteoclast activity is regulated by extracellular pH, whereby bone resorption is near-maximally activated at pH 7.0 but limited at ≥pH 7.4. This study examined the effects of low pH on osteoclast fusion, multi-nucleation, resorption and cell transcriptome. Osteoclasts were cultured on dentine discs at pH 7.4 (control) or pH 7.0 (acidified) for 5–7 days. Osteoclast number and resorptive activity were 1.9-fold and 6.7-fold higher, respectively, in acidified cultures. However, acidified osteoclasts were smaller, with fewer nuclei than controls (53 μm diameter with 9 ± 1 nuclei/cell versus 100 μm with 24 ± 3 nuclei/cell). mRNA expression analysis revealed that osteoclast formation and resorption-associated genes were increased in acidified osteoclasts. Switching mature osteoclasts formed for 5 days at pH 7.4 to acidified conditions decreased cell size 30 % within 4 h, resulting in a 2-fold increase in osteoclast numbers after 24 h. Resorptive activity in cells switched to pH 7.0 was visible within 8 h, and by 24 h resorption area was comparable to continually acidified osteoclasts. MicroCT analysis of dentine discs revealed 24-fold and 6.4-fold increases in resorption pit number in pH-switched osteoclasts relative to control and acidified cultures, respectively. RNAseq showed changes in extracellular pH differentially regulated gene expression, particularly metabolic and cell cycle-associated genes. Our results reveal previously unknown effects of extracellular pH on osteoclasts. Specifically, they show pH is an important modulator of osteoclast fusion and size that regulates the transcriptome. Furthermore, small changes in pH can induce significant morphological changes in osteoclasts and act as on/off switch between formation and resorption in ≤4 h.

{"title":"Extracellular pH is a critical regulator of osteoclast fusion, size and activation","authors":"Bethan K. Davies , Andrew J. Skelton , Mark Hopkinson , Simon Lumb , Gill Holdsworth , Timothy R. Arnett , Isabel R. Orriss","doi":"10.1016/j.bone.2025.117466","DOIUrl":"10.1016/j.bone.2025.117466","url":null,"abstract":"<div><div>Osteoclast activity is regulated by extracellular pH, whereby bone resorption is near-maximally activated at pH 7.0 but limited at ≥pH 7.4. This study examined the effects of low pH on osteoclast fusion, multi-nucleation, resorption and cell transcriptome. Osteoclasts were cultured on dentine discs at pH 7.4 (control) or pH 7.0 (acidified) for 5–7 days. Osteoclast number and resorptive activity were 1.9-fold and 6.7-fold higher, respectively, in acidified cultures. However, acidified osteoclasts were smaller, with fewer nuclei than controls (53 μm diameter with 9 ± 1 nuclei/cell versus 100 μm with 24 ± 3 nuclei/cell). mRNA expression analysis revealed that osteoclast formation and resorption-associated genes were increased in acidified osteoclasts. Switching mature osteoclasts formed for 5 days at pH 7.4 to acidified conditions decreased cell size 30 % within 4 h, resulting in a 2-fold increase in osteoclast numbers after 24 h. Resorptive activity in cells switched to pH 7.0 was visible within 8 h, and by 24 h resorption area was comparable to continually acidified osteoclasts. MicroCT analysis of dentine discs revealed 24-fold and 6.4-fold increases in resorption pit number in pH-switched osteoclasts relative to control and acidified cultures, respectively. RNAseq showed changes in extracellular pH differentially regulated gene expression, particularly metabolic and cell cycle-associated genes. Our results reveal previously unknown effects of extracellular pH on osteoclasts. Specifically, they show pH is an important modulator of osteoclast fusion and size that regulates the transcriptome. Furthermore, small changes in pH can induce significant morphological changes in osteoclasts and act as on/off switch between formation and resorption in ≤4 h.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"195 ","pages":"Article 117466"},"PeriodicalIF":3.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674701","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}

引用次数: 0

Altered vertebral biomechanical properties in prostate cancer patients following androgen deprivation therapy 前列腺癌患者接受雄激素剥夺疗法后脊椎生物力学特性的改变。

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2025-03-19 DOI: 10.1016/j.bone.2025.117465

Fiona G. Gibson , Margaret A. Paggiosi , Catherine Handforth , Janet E. Brown , Xinshan Li , Enrico Dall'Ara , Stefaan W. Verbruggen

Androgen deprivation therapy (ADT) for localised and metastatic prostate cancer (PCa) is known to improve survival in patients but has been associated with negative long-term impacts on the skeleton, including decreased bone mineral density (BMD) and increased fracture risk. Generally, dual-enery X-ray absorptiometry (DXA) measurements of areal BMD (aBMD) of vertebrae are used clinically to assess bone health. However, a prediction of vertebral bone strength requires information that aBMD cannot provide, such as geometry and volumetric BMD (vBMD). This study aims to investigate the effect of ADT on the densitometric (aBMD, trabecular vBMD, integral vBMD) and mechanical integrity (failure load and failure strength) of vertebrae, using a combination of DXA, quantitative computed tomography (QCT) and finite element (FE) modelling. For the FE analyses, 3D models were reconstructed from QCT images of 26 ADT treated patients, and their matched controls, collected as part of the ANTELOPE clinical trial. The ADT treated group experienced significantly decreased trabecular and integral vBMD (trabecular vBMD: −18 %, p < 0.001, integral vBMD: −11 %, p < 0.001) compared to control patients that showed no significant temporal changes (trabecular vBMD p = 0.037, integral vBMD p = 0.56). A similar trend was seen in the ADT treated group for the failure load and failure strength, where a decrease of 14 % was observed (p < 0.001). When comparing the proficiency in predicting the mechanical properties from densitometric properties, the integral vBMD performed best in the pooled data (r = 0.86–0.87, p < 0.001) closely followed by trabecular vBMD (r = 0.73–0.75, p < 0.001) with aBMD having a much weaker predictive ability (r = 0.19–0.21, p < 0.01). In conclusion, ADT significantly reduced both the densitometric properties and the mechanical strength of vertebrae. A stronger relationship between both trabecular vBMD and integral vBMD with the mechanical properties than the aBMD was observed, suggesting that such clinical measurements could improve predictions of fracture risk in prostate cancer patients treated with ADT.

{"title":"Altered vertebral biomechanical properties in prostate cancer patients following androgen deprivation therapy","authors":"Fiona G. Gibson , Margaret A. Paggiosi , Catherine Handforth , Janet E. Brown , Xinshan Li , Enrico Dall'Ara , Stefaan W. Verbruggen","doi":"10.1016/j.bone.2025.117465","DOIUrl":"10.1016/j.bone.2025.117465","url":null,"abstract":"<div><div>Androgen deprivation therapy (ADT) for localised and metastatic prostate cancer (PCa) is known to improve survival in patients but has been associated with negative long-term impacts on the skeleton, including decreased bone mineral density (BMD) and increased fracture risk. Generally, dual-enery X-ray absorptiometry (DXA) measurements of areal BMD (aBMD) of vertebrae are used clinically to assess bone health. However, a prediction of vertebral bone strength requires information that aBMD cannot provide, such as geometry and volumetric BMD (vBMD). This study aims to investigate the effect of ADT on the densitometric (aBMD, trabecular vBMD, integral vBMD) and mechanical integrity (failure load and failure strength) of vertebrae, using a combination of DXA, quantitative computed tomography (QCT) and finite element (FE) modelling. For the FE analyses, 3D models were reconstructed from QCT images of 26 ADT treated patients, and their matched controls, collected as part of the ANTELOPE clinical trial. The ADT treated group experienced significantly decreased trabecular and integral vBMD (trabecular vBMD: −18 %, <em>p</em> < 0.001, integral vBMD: −11 %, p < 0.001) compared to control patients that showed no significant temporal changes (trabecular vBMD <em>p</em> = 0.037, integral vBMD <em>p</em> = 0.56). A similar trend was seen in the ADT treated group for the failure load and failure strength, where a decrease of 14 % was observed (<em>p</em> < 0.001). When comparing the proficiency in predicting the mechanical properties from densitometric properties, the integral vBMD performed best in the pooled data (<em>r</em> = 0.86–0.87, <em>p</em> < 0.001) closely followed by trabecular vBMD (<em>r</em> = 0.73–0.75, p < 0.001) with aBMD having a much weaker predictive ability (<em>r</em> = 0.19–0.21, <em>p</em> < 0.01). In conclusion, ADT significantly reduced both the densitometric properties and the mechanical strength of vertebrae. A stronger relationship between both trabecular vBMD and integral vBMD with the mechanical properties than the aBMD was observed, suggesting that such clinical measurements could improve predictions of fracture risk in prostate cancer patients treated with ADT.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"195 ","pages":"Article 117465"},"PeriodicalIF":3.5,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674494","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}

引用次数: 0

Klotho senses mechanical stimuli and modulates tension-induced osteogenesis

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone

Pub Date : 2025-03-19 DOI: 10.1016/j.bone.2025.117464

Xinrui Men, Wei-Cho Chiou, Xingjian Li, Qiming Li, Xinyi Chen, Kaiwen Zhang, Xiaoge Jiang, Song Chen

Delicate external mechanosensing, efficient intracellular mechanotransduction and effective alveolar bone remodeling lay the foundation of orthodontic tooth movement (OTM). Periodontal ligament stem cells (PDLSCs) are thought to be the primary cells that withstand mechanical stimuli and respond to biomechanical signals during orthodontic treatment. Nevertheless, the cellular and molecular mechanisms of orthodontic force-induced mechanosignaling and osteogenesis in PDLSCs still remain unclear. In the present study, we hypothesize that the ageing suppressor, Klotho, is correlated with orthodontic force-triggered mechanical signaling cascades, further contributing to alveolar bone remodeling. This study reveals that Klotho expression is notably upregulated via cytoskeletal-nuclei-mediated epigenetic modifications, consistent with osteogenic differentiation on the tension side during OTM. Additionally, Klotho deficiency undermines tensile force-induced new bone formation in NFκB- and PI3K/Akt-dependent manners. Notably, RNA sequencing (RNA-seq) results and targeted force application experiments unveil that Klotho not only functions as a downstream effector of external stress but also acts as an upstream regulator in mechanical signaling for the first time. In summary, we identify the indispensable role of Klotho in mechanotransduction and alveolar bone formation, which provide a latent target of linking cell senescence to mechanical force in future studies and offer novel insights into orthodontic force-induced tooth movement and bone remodeling.

{"title":"Klotho senses mechanical stimuli and modulates tension-induced osteogenesis","authors":"Xinrui Men, Wei-Cho Chiou, Xingjian Li, Qiming Li, Xinyi Chen, Kaiwen Zhang, Xiaoge Jiang, Song Chen","doi":"10.1016/j.bone.2025.117464","DOIUrl":"10.1016/j.bone.2025.117464","url":null,"abstract":"<div><div>Delicate external mechanosensing, efficient intracellular mechanotransduction and effective alveolar bone remodeling lay the foundation of orthodontic tooth movement (OTM). Periodontal ligament stem cells (PDLSCs) are thought to be the primary cells that withstand mechanical stimuli and respond to biomechanical signals during orthodontic treatment. Nevertheless, the cellular and molecular mechanisms of orthodontic force-induced mechanosignaling and osteogenesis in PDLSCs still remain unclear. In the present study, we hypothesize that the ageing suppressor, Klotho, is correlated with orthodontic force-triggered mechanical signaling cascades, further contributing to alveolar bone remodeling. This study reveals that Klotho expression is notably upregulated via cytoskeletal-nuclei-mediated epigenetic modifications, consistent with osteogenic differentiation on the tension side during OTM. Additionally, Klotho deficiency undermines tensile force-induced new bone formation in NFκB- and PI3K/Akt-dependent manners. Notably, RNA sequencing (RNA-seq) results and targeted force application experiments unveil that Klotho not only functions as a downstream effector of external stress but also acts as an upstream regulator in mechanical signaling for the first time. In summary, we identify the indispensable role of Klotho in mechanotransduction and alveolar bone formation, which provide a latent target of linking cell senescence to mechanical force in future studies and offer novel insights into orthodontic force-induced tooth movement and bone remodeling.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"195 ","pages":"Article 117464"},"PeriodicalIF":3.5,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674932","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}

引用次数: 0