The global aging crisis has increased the prevalence of skeletal disorders, necessitating innovative therapeutic strategies. This review employs the brain-bone axis (BBA) framework to examine the role of the sympathetic nervous system (SNS) in bone metabolism. The research systematically elucidates the molecular mechanisms by which the SNS mediates signaling pathways through neurofibers and neurotransmitters, such as norepinephrine, dopamine, neuropeptide Y, and leptin, regulating interactions between bone-related cells to maintain skeletal homeostasis. It also identifies the pathological associations between the dysregulation of these pathways and the progression of bone-related conditions, such as osteoporosis, osteoarthritis, and intervertebral disc degeneration. By integrating current evidence, we identify novel therapeutic targets within the BBA and propose neuro-centric intervention strategies to mitigate skeletal diseases. This review deepens the understanding of neuro-skeletal interactions and lays a foundation for innovative treatments for bone-related pathologies.
{"title":"Molecular mechanisms and therapeutic implications of the sympathetic nervous system in bone-related disorders: a brain-bone axis perspective.","authors":"Mingdong Liu, Yaqi Liu, Jiayao Yu, Jiaqi Gong, Chunguang Zhao, Zheng Liu","doi":"10.1038/s41413-025-00494-1","DOIUrl":"10.1038/s41413-025-00494-1","url":null,"abstract":"<p><p>The global aging crisis has increased the prevalence of skeletal disorders, necessitating innovative therapeutic strategies. This review employs the brain-bone axis (BBA) framework to examine the role of the sympathetic nervous system (SNS) in bone metabolism. The research systematically elucidates the molecular mechanisms by which the SNS mediates signaling pathways through neurofibers and neurotransmitters, such as norepinephrine, dopamine, neuropeptide Y, and leptin, regulating interactions between bone-related cells to maintain skeletal homeostasis. It also identifies the pathological associations between the dysregulation of these pathways and the progression of bone-related conditions, such as osteoporosis, osteoarthritis, and intervertebral disc degeneration. By integrating current evidence, we identify novel therapeutic targets within the BBA and propose neuro-centric intervention strategies to mitigate skeletal diseases. This review deepens the understanding of neuro-skeletal interactions and lays a foundation for innovative treatments for bone-related pathologies.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"13 1","pages":"98"},"PeriodicalIF":15.0,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12669603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145653512","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}
Survival of motor neuron (SMN) protein encoded by SMN1 gene, is the essential and ubiquitously expressed protein in all tissues. Prior studies demonstrated that SMN deficiency impaired bone development, but the underlying mechanism of abnormal endochondral ossification remains obscure. Here, we showed SMN is involved in hypertrophic chondrocytes differentiation through regulating RNA splicing and protein degradation via analyzing single cell RNA-sequencing data of hypertrophic chondrocytes. Of note, SMN loss induced dwarfism and delayed endochondral ossification in Smn1 depletion-severe spinal muscular atrophy (SMA) mouse model and Smn1 chondrocyte conditional knockdown mouse. Histological analysis revealed that SMN deficiency expanded the zone of hypertrophic chondrocytes in the growth plates, but delayed turnover from hypertrophic to ossification zone. Widespread changes in endochondral ossification related gene expression and alternative splicing profiles were identified via RNA sequencing of growth plate cartilages from SMA mice on postnatal day 4. Importantly, Mass spectrometry-based proteomics analysis elucidated Y-box-binding protein 1 (YBX1) as a vital SMN-binding factor, was decreased in SMA mice. YBX1 knockdown reproduced the aberrant gene expression and splicing changes observed in SMA growth plate cartilages. Comparing the binding proteins of SMN and YBX1 revealed TNF receptor-associated factor 6 (TRAF6), which promoted ubiquitination degradation of YBX1. By conditionally deleting Smn1 in chondrocytes of WT mice and overexpressing Smn1 in chondrocytes of SMA mice, we proved that SMN expression in chondrocytes is critical for hypertrophic chondrocyte-mediated endochondral ossification. Collectively, these results demonstrate that SMN deficiency contributes to rapid systemic bone dysplasia syndrome by promoting TRAF6-induced ubiquitination degradation of YBX1 in growth plate cartilages of SMA mice.
由SMN1基因编码的运动神经元存活蛋白（Survival of motor neuron， SMN）是所有组织中必不可少且普遍表达的蛋白。先前的研究表明，SMN缺乏会损害骨发育，但异常软骨内成骨的潜在机制尚不清楚。在这里，我们通过分析增生性软骨细胞的单细胞RNA测序数据，发现SMN通过调节RNA剪接和蛋白质降解参与了增生性软骨细胞的分化。值得注意的是，Smn1缺失在Smn1缺失-严重脊髓性肌萎缩症（SMA）小鼠模型和Smn1软骨细胞条件敲低小鼠中诱导侏儒症和软骨内成骨延迟。组织学分析显示，SMN缺乏扩大了生长板中肥大软骨细胞区，但延迟了从肥大软骨细胞到骨化区的转变。通过对出生后第4天的SMA小鼠生长板软骨的RNA测序，发现软骨内成骨相关基因表达和剪接谱的广泛变化。重要的是，基于质谱的蛋白质组学分析阐明了y- box结合蛋白1 （YBX1）作为重要的smn结合因子，在SMA小鼠中减少。YBX1基因敲低可复制SMA生长板软骨中观察到的异常基因表达和剪接变化。比较SMN和YBX1的结合蛋白发现TNF受体相关因子6 （TRAF6）促进YBX1的泛素化降解。通过有条件地删除WT小鼠软骨细胞中的Smn1，并在SMA小鼠软骨细胞中过表达Smn1，我们证明了SMN在软骨细胞中的表达对于肥大软骨细胞介导的软骨内成骨至关重要。综上所述，这些结果表明SMN缺乏通过促进traf6诱导的SMA小鼠生长板软骨中YBX1的泛素化降解而导致快速的全身性骨发育不良综合征。
{"title":"SMN deficiency inhibits endochondral ossification via promoting TRAF6-induced ubiquitination degradation of YBX1 in spinal muscular atrophy.","authors":"Zijie Zhou,Xinbin Fan,Taiyang Xiang,Yinxuan Suo,Xiaoyan Shi,Yaoyao Li,Yimin Hua,Lei Sheng,Xiaozhong Zhou","doi":"10.1038/s41413-025-00473-6","DOIUrl":"https://doi.org/10.1038/s41413-025-00473-6","url":null,"abstract":"Survival of motor neuron (SMN) protein encoded by SMN1 gene, is the essential and ubiquitously expressed protein in all tissues. Prior studies demonstrated that SMN deficiency impaired bone development, but the underlying mechanism of abnormal endochondral ossification remains obscure. Here, we showed SMN is involved in hypertrophic chondrocytes differentiation through regulating RNA splicing and protein degradation via analyzing single cell RNA-sequencing data of hypertrophic chondrocytes. Of note, SMN loss induced dwarfism and delayed endochondral ossification in Smn1 depletion-severe spinal muscular atrophy (SMA) mouse model and Smn1 chondrocyte conditional knockdown mouse. Histological analysis revealed that SMN deficiency expanded the zone of hypertrophic chondrocytes in the growth plates, but delayed turnover from hypertrophic to ossification zone. Widespread changes in endochondral ossification related gene expression and alternative splicing profiles were identified via RNA sequencing of growth plate cartilages from SMA mice on postnatal day 4. Importantly, Mass spectrometry-based proteomics analysis elucidated Y-box-binding protein 1 (YBX1) as a vital SMN-binding factor, was decreased in SMA mice. YBX1 knockdown reproduced the aberrant gene expression and splicing changes observed in SMA growth plate cartilages. Comparing the binding proteins of SMN and YBX1 revealed TNF receptor-associated factor 6 (TRAF6), which promoted ubiquitination degradation of YBX1. By conditionally deleting Smn1 in chondrocytes of WT mice and overexpressing Smn1 in chondrocytes of SMA mice, we proved that SMN expression in chondrocytes is critical for hypertrophic chondrocyte-mediated endochondral ossification. Collectively, these results demonstrate that SMN deficiency contributes to rapid systemic bone dysplasia syndrome by promoting TRAF6-induced ubiquitination degradation of YBX1 in growth plate cartilages of SMA mice.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"1 1","pages":"97"},"PeriodicalIF":12.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145645051","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}
Osteomyelitis remains a global challenge in the field of orthopedics. Even after standard debridement and antibiotic-assisted treatment, the long-term recurrence rate remains at 20%-30%. Given the dynamic changes in immune responses and defense mechanisms during bone infection, as well as the complex "race for the surface" involving bacterial adhesion and host cells (macrophages and tissue cells) on implant surfaces, biomaterials with immunomodulatory functions have attracted considerable attention. Macrophages, as crucial components of the immune system, participate in the inflammatory regulation and tissue remodeling of bone infections through highly plastic polarization mechanisms after bacterial invasion. The different microenvironmental characteristics and therapeutic needs at different stages of bone infection highlight the promising applications of biomaterials capable of macrophage polarization remodeling and sequential regulation. In this review, we provide a detailed discussion of the complex immune regulatory patterns in the bone infection microenvironment and the critical functions of macrophage polarization. We then explore how implant surface properties influence bacterial adhesion and macrophage function, highlighting the importance of achieving precise and dynamic regulation of macrophage polarization based on the Race for the Surface theory. Furthermore, we focus on recent advances, potential challenges, and opportunities in biomaterial-mediated macrophage polarization remodeling and sequential modulation strategies across different stages of osteomyelitis, aiming to offer insights that may accelerate the clinical translation of novel biomaterial-based macrophage immunotherapies.
{"title":"Biomaterial-mediated macrophage polarization remodeling and sequential regulation: a potential strategy in bone infections treatment.","authors":"Xiangwen Shi,Chao Xu,Zhian Chen,Mingjun Li,Zhe Yin,Bin Wang,Yang Li,Yipeng Wu,Xiaopei Wu,Yongqing Xu","doi":"10.1038/s41413-025-00471-8","DOIUrl":"https://doi.org/10.1038/s41413-025-00471-8","url":null,"abstract":"Osteomyelitis remains a global challenge in the field of orthopedics. Even after standard debridement and antibiotic-assisted treatment, the long-term recurrence rate remains at 20%-30%. Given the dynamic changes in immune responses and defense mechanisms during bone infection, as well as the complex \"race for the surface\" involving bacterial adhesion and host cells (macrophages and tissue cells) on implant surfaces, biomaterials with immunomodulatory functions have attracted considerable attention. Macrophages, as crucial components of the immune system, participate in the inflammatory regulation and tissue remodeling of bone infections through highly plastic polarization mechanisms after bacterial invasion. The different microenvironmental characteristics and therapeutic needs at different stages of bone infection highlight the promising applications of biomaterials capable of macrophage polarization remodeling and sequential regulation. In this review, we provide a detailed discussion of the complex immune regulatory patterns in the bone infection microenvironment and the critical functions of macrophage polarization. We then explore how implant surface properties influence bacterial adhesion and macrophage function, highlighting the importance of achieving precise and dynamic regulation of macrophage polarization based on the Race for the Surface theory. Furthermore, we focus on recent advances, potential challenges, and opportunities in biomaterial-mediated macrophage polarization remodeling and sequential modulation strategies across different stages of osteomyelitis, aiming to offer insights that may accelerate the clinical translation of novel biomaterial-based macrophage immunotherapies.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"71 1","pages":"96"},"PeriodicalIF":12.7,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599963","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}
Bone marrow lesions (BML) are early signs of osteoarthritis (OA) and are strongly correlated with the deterioration of cartilage lesions. Single-cell RNA sequencing (scRNA-seq) analyses were performed on BM from non-BML and BML areas and articular cartilage from intact and damaged areas to explore BML landscape and BML-cartilage crosstalk. We revealed the immune landscape of BM in non-BML and BML, and the transition to pro-inflammatory states of clusters in BMLs, such as classical monocytes and non-classical monocytes. Non-classical monocytes have high inflammation, OA gene signatures, and senescence scores, and are potential primary clusters promoting OA progression. Histological signs of OA related to the cellular landscape in damaged cartilage were identified, including PreFC exhaustion. The BM-cartilage crosstalk at the cell-cell interaction (CCIs) level and the TNF signal transmitted by non-classical monocytes are the critical CCIs in BML-induced cartilage damage, and PreFC is one of the primary receivers of the signal. We further validated the higher senescence level of non-classical monocyte and FC-2 in OA mice, compared with classical monocyte and PreFC, respectively. Transcription factor 7 like 2 (TCF7L2) was identified as a shared transcription factor in the senescence of monocytes and chondrocytes, facilitating the development of the senescence-associated secretory phenotype (SASP). Therefore, senescent non-classical monocytes promote BMLs and inflammation and senescence of chondrocytes by modulating BML-cartilage crosstalk in OA, with TCF7L2 serving as a regulator.
骨髓病变（BML）是骨关节炎（OA）的早期症状，与软骨病变的恶化密切相关。单细胞RNA测序（scRNA-seq）分析来自非BML和BML区域的BM以及来自完整和受损区域的关节软骨，以探索BML景观和BML-软骨串扰。我们揭示了非BML和BML中BM的免疫景观，以及BML中群集（如经典单核细胞和非经典单核细胞）向促炎状态的转变。非经典单核细胞具有高炎症、OA基因特征和衰老评分，是促进OA进展的潜在原发性集群。骨性关节炎的组织学征象与受损软骨的细胞景观有关，包括PreFC衰竭。细胞-细胞相互作用（CCIs）水平的bm -软骨串扰和非经典单核细胞传递的TNF信号是bml诱导软骨损伤的关键CCIs，而PreFC是该信号的主要受体之一。我们进一步验证了OA小鼠非经典单核细胞和FC-2的衰老水平分别高于经典单核细胞和PreFC。转录因子7 like 2 （TCF7L2）被确定为单核细胞和软骨细胞衰老的共享转录因子，促进衰老相关分泌表型（senescence associated secretory phenotype， SASP）的发展。因此，衰老的非经典单核细胞通过调节骨髓瘤-软骨串扰促进骨髓瘤和软骨细胞的炎症和衰老，而TCF7L2是一个调节因子。
{"title":"Single-cell sequencing reveals a senescent immune landscape in bone marrow lesions inducing articular cartilage damage in osteoarthritis.","authors":"Pengqiang Lou,Xiaoyan Lu,Mengyin Li,Yue Yao,Xin Shao,Dan Shou,Xiaohui Fan,Peijian Tong,Yang Zhang","doi":"10.1038/s41413-025-00467-4","DOIUrl":"https://doi.org/10.1038/s41413-025-00467-4","url":null,"abstract":"Bone marrow lesions (BML) are early signs of osteoarthritis (OA) and are strongly correlated with the deterioration of cartilage lesions. Single-cell RNA sequencing (scRNA-seq) analyses were performed on BM from non-BML and BML areas and articular cartilage from intact and damaged areas to explore BML landscape and BML-cartilage crosstalk. We revealed the immune landscape of BM in non-BML and BML, and the transition to pro-inflammatory states of clusters in BMLs, such as classical monocytes and non-classical monocytes. Non-classical monocytes have high inflammation, OA gene signatures, and senescence scores, and are potential primary clusters promoting OA progression. Histological signs of OA related to the cellular landscape in damaged cartilage were identified, including PreFC exhaustion. The BM-cartilage crosstalk at the cell-cell interaction (CCIs) level and the TNF signal transmitted by non-classical monocytes are the critical CCIs in BML-induced cartilage damage, and PreFC is one of the primary receivers of the signal. We further validated the higher senescence level of non-classical monocyte and FC-2 in OA mice, compared with classical monocyte and PreFC, respectively. Transcription factor 7 like 2 (TCF7L2) was identified as a shared transcription factor in the senescence of monocytes and chondrocytes, facilitating the development of the senescence-associated secretory phenotype (SASP). Therefore, senescent non-classical monocytes promote BMLs and inflammation and senescence of chondrocytes by modulating BML-cartilage crosstalk in OA, with TCF7L2 serving as a regulator.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"107 1","pages":"94"},"PeriodicalIF":12.7,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145568163","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}
Pub Date : 2025-11-17DOI: 10.1038/s41413-025-00464-7
Jun Chen,Xinquan Jiang
Osteoporosis is a prevalent metabolic bone disorder that develops when osteoclast-mediated bone resorption chronically exceeds osteoblast-driven bone formation. The molecular pathways that govern osteogenic dysfunction and connect cellular metabolism to differentiation regulation remain poorly characterized. Here, we identify Sirtuin 5 (Sirt5) as a pivotal osteogenic regulator through bioinformatic screening and functional validation in Sirt5-knockout mice. Mechanistically, Sirt5 governs mitochondrial homeostasis by desuccinylating Solute Carrier Family 25 Member 4 (Slc25a4) at lysine 147 (K147), as demonstrated by quantitative succinylome profiling and site-directed mutagenesis. This site-specific desuccinylation triggers Slc25a4 degradation, attenuating mitochondrial oxidative stress and promoting osteoblast differentiation. Crucially, Slc25a4-K147 succinylation drives osteoporosis progression, while Sirt5-mediated desuccinylation at this site confers protection. Our work reveals the Sirt5-Slc25a4-K147 axis as a novel regulatory mechanism coupling mitochondrial metabolism to bone homeostasis, offering a therapeutic target for osteoporosis intervention.
{"title":"Sirtuin 5-mediated desuccinylation of Slc25a4 inhibits osteoporosis by enhancing mitochondrial respiration.","authors":"Jun Chen,Xinquan Jiang","doi":"10.1038/s41413-025-00464-7","DOIUrl":"https://doi.org/10.1038/s41413-025-00464-7","url":null,"abstract":"Osteoporosis is a prevalent metabolic bone disorder that develops when osteoclast-mediated bone resorption chronically exceeds osteoblast-driven bone formation. The molecular pathways that govern osteogenic dysfunction and connect cellular metabolism to differentiation regulation remain poorly characterized. Here, we identify Sirtuin 5 (Sirt5) as a pivotal osteogenic regulator through bioinformatic screening and functional validation in Sirt5-knockout mice. Mechanistically, Sirt5 governs mitochondrial homeostasis by desuccinylating Solute Carrier Family 25 Member 4 (Slc25a4) at lysine 147 (K147), as demonstrated by quantitative succinylome profiling and site-directed mutagenesis. This site-specific desuccinylation triggers Slc25a4 degradation, attenuating mitochondrial oxidative stress and promoting osteoblast differentiation. Crucially, Slc25a4-K147 succinylation drives osteoporosis progression, while Sirt5-mediated desuccinylation at this site confers protection. Our work reveals the Sirt5-Slc25a4-K147 axis as a novel regulatory mechanism coupling mitochondrial metabolism to bone homeostasis, offering a therapeutic target for osteoporosis intervention.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"15 1","pages":"93"},"PeriodicalIF":12.7,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531251","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}
Pub Date : 2025-11-10DOI: 10.1038/s41413-025-00469-2
Shiju Song,Jing Fan,Guangyu Ding,Jinhua Yin,Weiguang Lu,Liangjie Huang,Jingyan Hu,Xueqin Gong,Bo Gao,Qiang Jie,Kathryn Song Eng Cheah,Chao Zheng,Liu Yang
Hypertrophic chondrocytes (HCs) could transform into osteoblastic lineage cells while the pathophysiological implications of HC transformation remain largely unknown. Here, we generated a mouse line utilizing Col10a1-Cre to induce DTA expression to genetically ablate HCs and their descendants. Col10a1-Cre; R26DTA/+ mice displayed dwarf phenotype, abnormal spongy bone, and significantly delayed drill-hole injuries healing, suggesting an indispensable role of HC lineage extension in bone growth and injury repair. Intriguingly, single-cell RNA sequencing analysis revealed the most significant loss of a cell cluster expressing multiple angiogenic factors (Pro-Angiogenic Descendants of HCs, PADs) among cells derived from Col10a1-Cre; R26DTA/+ and control femurs. In silico analysis of cell-cell communication supported Thrombospondin 4 (THBS4) as a specific angiogenic factor mediating the crosstalk between PADs and vascular endothelial cells. Concordantly, analyses using immunostaining combined with tissue clearing revealed that PADs physically contacted with endothelial cells, whereas Col10a1-Cre; R26DTA/+ mice showed defective metaphyseal and cortical vessel formation and post-injury angiogenesis along with a significant loss of THBS4. Moreover, in vitro assays showed that supplying THBS4 was sufficient to promote proliferation and tube formation of endothelial cells and rescue defective angiogenesis of Col10a1-Cre; R26DTA/+ metatarsal explants. Collectively, these findings demonstrate a critical role of PADs in bone growth and injury repair by secreting THBS4 to regulate angiogenesis.
{"title":"Descendants of hypertrophic chondrocytes promote angiogenesis by secreting THBS4 during bone growth and injury repair.","authors":"Shiju Song,Jing Fan,Guangyu Ding,Jinhua Yin,Weiguang Lu,Liangjie Huang,Jingyan Hu,Xueqin Gong,Bo Gao,Qiang Jie,Kathryn Song Eng Cheah,Chao Zheng,Liu Yang","doi":"10.1038/s41413-025-00469-2","DOIUrl":"https://doi.org/10.1038/s41413-025-00469-2","url":null,"abstract":"Hypertrophic chondrocytes (HCs) could transform into osteoblastic lineage cells while the pathophysiological implications of HC transformation remain largely unknown. Here, we generated a mouse line utilizing Col10a1-Cre to induce DTA expression to genetically ablate HCs and their descendants. Col10a1-Cre; R26DTA/+ mice displayed dwarf phenotype, abnormal spongy bone, and significantly delayed drill-hole injuries healing, suggesting an indispensable role of HC lineage extension in bone growth and injury repair. Intriguingly, single-cell RNA sequencing analysis revealed the most significant loss of a cell cluster expressing multiple angiogenic factors (Pro-Angiogenic Descendants of HCs, PADs) among cells derived from Col10a1-Cre; R26DTA/+ and control femurs. In silico analysis of cell-cell communication supported Thrombospondin 4 (THBS4) as a specific angiogenic factor mediating the crosstalk between PADs and vascular endothelial cells. Concordantly, analyses using immunostaining combined with tissue clearing revealed that PADs physically contacted with endothelial cells, whereas Col10a1-Cre; R26DTA/+ mice showed defective metaphyseal and cortical vessel formation and post-injury angiogenesis along with a significant loss of THBS4. Moreover, in vitro assays showed that supplying THBS4 was sufficient to promote proliferation and tube formation of endothelial cells and rescue defective angiogenesis of Col10a1-Cre; R26DTA/+ metatarsal explants. Collectively, these findings demonstrate a critical role of PADs in bone growth and injury repair by secreting THBS4 to regulate angiogenesis.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"108 1","pages":"92"},"PeriodicalIF":12.7,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477745","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}
Circadian rhythm disorders are associated with dysfunction in inflammatory diseases, and targeted regulation of the circadian rhythm could serve as an intervention strategy. RORα/γ, as core components of circadian clock genes, positively modulate the key circadian molecule BMAL1. In this study, Gala-SR, a potent small-molecule compound designed to effectively regulate circadian rhythms, was synthesized through a monosaccharide modification prodrug strategy via a hydrolysable conjugation of galactose onto SR1078, an unique synthetic agonist of RORα/γ. Compared with SR1078, Gala-SR exhibited significantly greater aqueous solubility, cytocompatibility, pharmacokinetic characteristics and efficacy in the targeted activation of RORα. Importantly, Gala-SR ameliorated rhythm disorders by enhancing amplitude of the circadian rhythm both in vitro and in vivo. In circadian rhythm disordered mice with periodontitis, Gala-SR restored local circadian rhythm and mitigated inflammation in periodontal tissue in a circadian clock-dependent manner, and alleviated alveolar bone loss. Our study demonstrates that Gala-SR exhibits great promise in restoration of circadian rhythm and could potentially serve as a targeted therapeutic intervention for treating inflammatory diseases arising from disruptions in circadian rhythm. This work provides a feasible paradigm for the development and translational application of small molecule modulators targeting circadian rhythms.
{"title":"Galactose-modified small molecule modulator targets RORα to enhance circadian rhythm and alleviate periodontitis-associated alveolar bone loss.","authors":"Guangxia Feng,Zhiwen Liao,Yifan Wang,Qingming Tang,Nayun Li,Cheng Li,Yuqing Liu,Renlong Liu,Mingjian Cui,Wenjie Fan,Ying Yin,Lingkui Meng,Jing Zeng,Zetao Chen,Guanzheng Luo,Peng Xiang,Qian Wan,Lili Chen","doi":"10.1038/s41413-025-00445-w","DOIUrl":"https://doi.org/10.1038/s41413-025-00445-w","url":null,"abstract":"Circadian rhythm disorders are associated with dysfunction in inflammatory diseases, and targeted regulation of the circadian rhythm could serve as an intervention strategy. RORα/γ, as core components of circadian clock genes, positively modulate the key circadian molecule BMAL1. In this study, Gala-SR, a potent small-molecule compound designed to effectively regulate circadian rhythms, was synthesized through a monosaccharide modification prodrug strategy via a hydrolysable conjugation of galactose onto SR1078, an unique synthetic agonist of RORα/γ. Compared with SR1078, Gala-SR exhibited significantly greater aqueous solubility, cytocompatibility, pharmacokinetic characteristics and efficacy in the targeted activation of RORα. Importantly, Gala-SR ameliorated rhythm disorders by enhancing amplitude of the circadian rhythm both in vitro and in vivo. In circadian rhythm disordered mice with periodontitis, Gala-SR restored local circadian rhythm and mitigated inflammation in periodontal tissue in a circadian clock-dependent manner, and alleviated alveolar bone loss. Our study demonstrates that Gala-SR exhibits great promise in restoration of circadian rhythm and could potentially serve as a targeted therapeutic intervention for treating inflammatory diseases arising from disruptions in circadian rhythm. This work provides a feasible paradigm for the development and translational application of small molecule modulators targeting circadian rhythms.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"74 1","pages":"91"},"PeriodicalIF":12.7,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145403834","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}
Ossification of the posterior longitudinal ligament (OPLL) is a degenerative disease characterized by progressive ectopic bone formation process, which can lead to severe neurological impairments and reduced quality of life. While the etiology of OPLL is generally considered multifactorial, there is no consensus regarding these contributing factors including genetic, endocrine, biomechanical, immune and lifestyle factors. Through accumulating evidence from multidisciplinary investigations, the pathophysiological connection between OPLL and endocrine-metabolic dysregulation is becoming increasingly clear. Nevertheless, comprehensive understanding of the relationship between the two is hindered by several problems, such as methodological limitations and inadequate mechanistic studies. This review takes a deep dive into the possible factors contributing to OPLL from all aspects of metabolism, including glucose metabolism, lipid metabolism, bone and mineral metabolism, leptin, vitamin, growth hormone/IGF-1 and sex hormones, highlighting their potential roles in the onset and progression of OPLL. Clarifying the etiology of OPLL and elucidating the underlying pathogenesis are crucial for advancing both early intervention strategies and therapeutic approaches in clinical management. Therefore, the endocrine and metabolic disorders in OPLL patients should become a focus of future research.
{"title":"The relationship between OPLL and metabolic disorders.","authors":"Junfeng Wang,Ziheng Wei,Qingjie Kong,Yanqing Sun,Zhichao Zhang,Haiyuan Yang,Xiongsheng Chen","doi":"10.1038/s41413-025-00446-9","DOIUrl":"https://doi.org/10.1038/s41413-025-00446-9","url":null,"abstract":"Ossification of the posterior longitudinal ligament (OPLL) is a degenerative disease characterized by progressive ectopic bone formation process, which can lead to severe neurological impairments and reduced quality of life. While the etiology of OPLL is generally considered multifactorial, there is no consensus regarding these contributing factors including genetic, endocrine, biomechanical, immune and lifestyle factors. Through accumulating evidence from multidisciplinary investigations, the pathophysiological connection between OPLL and endocrine-metabolic dysregulation is becoming increasingly clear. Nevertheless, comprehensive understanding of the relationship between the two is hindered by several problems, such as methodological limitations and inadequate mechanistic studies. This review takes a deep dive into the possible factors contributing to OPLL from all aspects of metabolism, including glucose metabolism, lipid metabolism, bone and mineral metabolism, leptin, vitamin, growth hormone/IGF-1 and sex hormones, highlighting their potential roles in the onset and progression of OPLL. Clarifying the etiology of OPLL and elucidating the underlying pathogenesis are crucial for advancing both early intervention strategies and therapeutic approaches in clinical management. Therefore, the endocrine and metabolic disorders in OPLL patients should become a focus of future research.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"11 1","pages":"90"},"PeriodicalIF":12.7,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145357869","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}
Pub Date : 2025-10-21DOI: 10.1038/s41413-025-00472-7
Giselle Kaneda,Lea Zila,Jacob T Wechsler,Karim Shafi,Karandeep Cheema,Hyun Bae,Sang D Kim,Alexander Tuchman,Debiao Li,Dmitriy Sheyn
Chronic lower back pain (LBP) is the leading cause of disability worldwide. Due to its close relationship with intervertebral disc (IVD) degeneration (IVDD), research has historically focused more on understanding the mechanism behind IVDD while clinical efforts prioritize pain management. More recently, there has been a shift toward understanding LBP as a distinct pathological entity. This review synthesizes current knowledge on discogenic LBP, combining known pathophysiology, molecular mechanisms, risk factors, diagnostic challenges, and available experimental models. IVDD is a complex, multifactorial process involving biochemical, mechanical, and inflammatory changes within the disc, leading to structural breakdown and potential discogenic pain. Key mechanisms include extracellular matrix degradation, upregulation of inflammatory mediators, immune cell infiltration, and aberrant nerve and vascular ingrowth. However, not all cases of IVDD result in LBP, highlighting the need for further investigation into the cellular, molecular, and biomechanical factors contributing to symptom development. Current diagnostic tools and experimental models for studying discogenic LBP remain limited, impeding the development of targeted treatments. Existing therapies primarily focus on symptom management rather than addressing underlying disease mechanisms.
{"title":"What a pain in the back: etiology, diagnosis and future treatment directions for discogenic low back pain.","authors":"Giselle Kaneda,Lea Zila,Jacob T Wechsler,Karim Shafi,Karandeep Cheema,Hyun Bae,Sang D Kim,Alexander Tuchman,Debiao Li,Dmitriy Sheyn","doi":"10.1038/s41413-025-00472-7","DOIUrl":"https://doi.org/10.1038/s41413-025-00472-7","url":null,"abstract":"Chronic lower back pain (LBP) is the leading cause of disability worldwide. Due to its close relationship with intervertebral disc (IVD) degeneration (IVDD), research has historically focused more on understanding the mechanism behind IVDD while clinical efforts prioritize pain management. More recently, there has been a shift toward understanding LBP as a distinct pathological entity. This review synthesizes current knowledge on discogenic LBP, combining known pathophysiology, molecular mechanisms, risk factors, diagnostic challenges, and available experimental models. IVDD is a complex, multifactorial process involving biochemical, mechanical, and inflammatory changes within the disc, leading to structural breakdown and potential discogenic pain. Key mechanisms include extracellular matrix degradation, upregulation of inflammatory mediators, immune cell infiltration, and aberrant nerve and vascular ingrowth. However, not all cases of IVDD result in LBP, highlighting the need for further investigation into the cellular, molecular, and biomechanical factors contributing to symptom development. Current diagnostic tools and experimental models for studying discogenic LBP remain limited, impeding the development of targeted treatments. Existing therapies primarily focus on symptom management rather than addressing underlying disease mechanisms.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"12 1","pages":"89"},"PeriodicalIF":12.7,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338687","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}
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