Bone Research最新文献

{"title":"Nucleic acid aptamers in orthopedic diseases: promising therapeutic agents for bone disorders","authors":"Zhenhong He, Qingping Peng, Wenying Bin, Luyao Zhao, Yihuang Chen, Yuanqun Zhang, Weihu Yang, Xingchen Yan, Huan Liu","doi":"10.1038/s41413-025-00447-8","DOIUrl":"https://doi.org/10.1038/s41413-025-00447-8","url":null,"abstract":"<p>Precision medicine has become a cornerstone in modern therapeutic strategies, with nucleic acid aptamers emerging as pivotal tools due to their unique properties. These oligonucleotide fragments, selected through the Systematic Evolution of Ligands by Exponential Enrichment process, exhibit high affinity and specificity toward their targets, such as DNA, RNA, proteins, and other biomolecules. Nucleic acid aptamers offer significant advantages over traditional therapeutic agents, including superior biological stability, minimal immunogenicity, and the capacity for universal chemical modifications that enhance their in vivo performance and targeting precision. In the realm of osseous tissue repair and regeneration, a complex physiological process essential for maintaining skeletal integrity, aptamers have shown remarkable potential in influencing molecular pathways crucial for bone regeneration, promoting osteogenic differentiation and supporting osteoblast survival. By engineering aptamers to regulate inflammatory responses and facilitate the proliferation and differentiation of fibroblasts, these oligonucleotides can be integrated into advanced drug delivery systems, significantly improving bone repair efficacy while minimizing adverse effects. Aptamer-mediated strategies, including the use of siRNA and miRNA mimics or inhibitors, have shown efficacy in enhancing bone mass and microstructure. These approaches hold transformative potential for treating a range of orthopedic conditions like osteoporosis, osteosarcoma, and osteoarthritis. This review synthesizes the molecular mechanisms and biological roles of aptamers in orthopedic diseases, emphasizing their potential to drive innovative and effective therapeutic interventions.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"16 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144694217","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}

{"title":"Osteoclast-independent osteocyte dendrite defects in mice bearing the osteogenesis imperfecta-causing Sp7 R342C mutation.","authors":"Jialiang S Wang,Katelyn Strauss,Caroline Houghton,Numa Islam,Sung-Hee Yoon,Tatsuya Kobayashi,Daniel J Brooks,Mary L Bouxsein,Yingshe Zhao,Cristal S Yee,Tamara N Alliston,Marc N Wein","doi":"10.1038/s41413-025-00440-1","DOIUrl":"https://doi.org/10.1038/s41413-025-00440-1","url":null,"abstract":"Osteogenesis imperfecta (OI) is a group of diseases caused by defects in type I collagen processing which result in skeletal fragility. While these disorders have been regarded as defects in osteoblast function, the role of matrix-embedded osteocytes in OI pathogenesis remains largely unknown. Homozygous human SP7 (c.946 C > T, R316C) mutation results in a recessive form of OI characterized by fragility fractures, low bone mineral density and osteocyte dendrite defects. To better understand how the OI-causing R316C mutation affects the function of SP7, we generated Sp7R342C knock-in mice. Consistent with patient phenotypes, Sp7R342C/R342C mice demonstrate increased cortical porosity and reduced cortical bone mineral density. Sp7R342C/R342C mice show osteocyte dendrite defects, increased osteocyte apoptosis, and intracortical bone remodeling with ectopic intracortical osteoclasts and elevated osteocyte Tnfsf11 expression. Remarkably, these defects in osteocyte function contrast to only mild changes in mature osteoblast function, suggesting that this Sp7 mutation selectively interferes with the function of Sp7 in osteocytes and mature osteoblasts, but not during early stages of osteoblast differentiation. Osteocyte morphology changes in Sp7R342C/R342C mice were not restored by inhibiting osteoclast formation, indicating that dendrite defects lie upstream of high intracortical osteoclast activity in this model. Moreover, transcriptomic profiling reveals that the expression of a core set osteocyte-enriched genes is highly dysregulated by the R342C mutation. Thus, this supports a model in which osteocyte dysfunction can drive OI pathogenesis and provides a valuable resource to test novel therapeutic approaches and to understand the osteocyte-specific role of SP7 in bone remodeling.","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"5 1","pages":"70"},"PeriodicalIF":12.7,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664280","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}

{"title":"Cellular senescence and other age-related mechanisms in skeletal diseases","authors":"Ke Li, Sihan Hu, Hao Chen","doi":"10.1038/s41413-025-00448-7","DOIUrl":"https://doi.org/10.1038/s41413-025-00448-7","url":null,"abstract":"<p>Cellular senescence and its senescence-associated secretory phenotype (SASP) represent a pivotal role in the development of skeletal diseases. Targeted elimination or rejuvenation of senescent cells has shown potential as a therapeutic strategy to reverse age-related skeletal senescence and promote bone regeneration. Meanwhile, other age-related mechanisms, involving altered cellular functions, impaired intercellular crosstalk, disturbed tissue microenvironment, and decreased regenerative capacity, synergistically contribute to the pathogenesis. In this review, we outline the cellular senescence and other age-related mechanisms in developing skeletal diseases, including osteoporosis, intervertebral disc degeneration, osteoarthritis, rheumatoid arthritis, bone tumors and ankylosing spondylitis, with the aim of comprehensively understanding their detrimental effects on the aged skeleton and screening the potential targets for anti-aging therapy within the skeletal system.</p><figure></figure>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"26 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144568324","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}

{"title":"Single-cell transcriptomic analysis identifies systemic immunosuppressive myeloid cells and local monocytes/macrophages as key regulators in polytrauma-induced immune dysregulation","authors":"Drishti Maniar, M. Cole Keenum, Casey E. Vantucci, Tyler Guyer, Paramita Chatterjee, Kelly Leguineche, Kaitlyn Cheung, Robert E. Guldberg, Krishnendu Roy","doi":"10.1038/s41413-025-00444-x","DOIUrl":"https://doi.org/10.1038/s41413-025-00444-x","url":null,"abstract":"<p>Polytrauma with significant bone and volumetric muscle loss presents substantial clinical challenges. Although immune responses significantly influence fracture healing post-polytrauma, the cellular and molecular underpinnings of polytrauma-induced immune dysregulation require further investigation. While previous studies examined either injury site tissue or systemic tissue (peripheral blood), our study uniquely investigated both systemic and local immune cells at the same time to better understand polytrauma-induced immune dysregulation and associated impaired bone healing. Using single-cell RNA sequencing (scRNA-seq) in a rat polytrauma model, we analyzed blood, bone marrow, and the local defect soft tissue to identify potential cellular and molecular targets involved in immune dysregulation. We identified a trauma-associated immunosuppressive myeloid (TIM) cell population that drives systemic immune dysregulation, immunosuppression, and potentially impaired bone healing. We found CD1d as a global marker for TIM cells in polytrauma. In the local defect tissue, we observed <i>Spp1</i>⁺ monocytes/macrophages mediating inflammatory, fibrotic, and impaired adaptive immune responses. Finally, our findings highlighted increased signaling via <i>Anxa1-Fpr2</i> and <i>Spp1-Cd44</i> axes. This comprehensive analysis enhances our understanding of immune dysregulation-mediated nonunion following traumatic injury and provides biomarkers that could function as treatment targets.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"111 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144568325","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}

{"title":"Reduced somatosensory innervation alters the skeletal transcriptome at a single cell level in a mouse model of type 2 diabetes.","authors":"Masnsen Cherief, Mario Gomez-Salazar, Minjung Kang, Seungyong Lee, Sowmya Ramesh, Qizhi Qin, Mingxin Xu, Soohyun Kim, Mary Archer, Manyu Zhu, Ahmet Hoke, Aaron W James","doi":"10.1038/s41413-025-00436-x","DOIUrl":"10.1038/s41413-025-00436-x","url":null,"abstract":"<p><p>Peripheral neuropathy is a common complication in diabetes, affecting around 50% of the diabetic population. Co-occurrence of diabetic peripheral neuropathy (DPN) and diabetic bone disease has led to the hypothesis that DPN influences bone metabolism, although little experimental evidence has yet supported this premise. To investigate, mice were fed a high-fat diet (HFD) followed by phenotyping of skeletal-innervating neurons and bone architectural parameters. Results showed that HFD feeding resulted in a marked decrease in skeletal innervation (69%-41% reduction in Beta-III-Tubulin-stained nerves, 38% reduction in CGRP-stained nerves in long bone periosteum). These changes in skeletal innervation were associated with significant alterations in bone mass and in cortical and trabecular bone microarchitecture of long bones. Single-cell RNA sequencing (scRNA-Seq) of sensory neurons and bone tissue was next utilized to reconstruct potential nerve-to-bone signaling interactions, including implication of sensory nerve-derived neurotrophins (Bdnf), neuropeptides (Gal, Calca and Calcb), and other morphogens (Vegfa, Pdgfa, and Angpt2). Moreover, scRNA-Seq identified marked shifts in periosteal cell transcriptional changes within HFD-fed conditions, including a reduction in cell proliferation, an increase in adipogenic differentiation markers, and reductions in WNT, TGFβ, and MAPK signaling activity. When isolated, periosteal cells from HFD-fed mice showed deficits in proliferative and osteogenic differentiation potential. Moreover, these cellular changes in proliferation and differentiation capacity were restored by treatment of HFD-exposed periosteal cells to sensory neuron-conditioned medium. In summary, HFD modeling of type 2 diabetes results in skeletal polyneuropathy. Moreover, the combination of multi-tissue scRNA-Seq and isolated in vitro studies strengthen the case for altered nerve-to-bone signaling in diabetic bone disease.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"13 1","pages":"67"},"PeriodicalIF":14.3,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12227694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564419","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}

{"title":"ER-induced PERK/TFEB cascade sequentially modulates mitochondrial dynamics during cranial suture expansion","authors":"Jingyi Cai, Ziyang Min, Chaoyuan Li, Zhihe Zhao, Jun Liu, Dian Jing","doi":"10.1038/s41413-025-00427-y","DOIUrl":"https://doi.org/10.1038/s41413-025-00427-y","url":null,"abstract":"<p>The effectiveness of cranial suture expansion therapy hinges on the timely and adequate regeneration of bone tissue in response to mechanical stimuli. To optimize clinical outcomes and prevent post-expansion relapse, we delved into the underlying mechanisms governing bone remodeling during the processes of suture expansion and relapse. Our findings revealed that in vitro stretching bolstered mesenchymal stem cells’ antioxidative and osteogenic capacity by orchestrating mitochondrial activities, which governed by force-induced endoplasmic reticulum (ER) stress. Nonetheless, this signal transduction occurred through the activation of protein kinase R-like ER kinase (PERK) at the ER-mitochondria interface, rather than ER-mitochondria calcium flow as previously reported. Subsequently, PERK activation triggered TFEB translocation to the nucleus, thus regulating mitochondrial dynamics transcriptionally. Assessment of the mitochondrial pool during expansion and relapse unveiled a sequential, two-phase regulation governed by the ER stress/p-PERK/TFEB signaling cascade. Initially, PERK activation facilitated TFEB nuclear localization, stimulating mitochondrial biogenesis through PGC1-α, thereby addressing energy demands during the initial phase. Subsequently, TFEB shifted focus towards ensuring adequate mitophagy for mitochondrial quality maintenance during the remodeling process. Premature withdrawal of expanding force disrupted this sequential regulation, leading to compromised mitophagy and the accumulation of dysfunctional mitochondria, culminating in suboptimal bone regeneration and relapse. Notably, pharmacological activation of mitophagy effectively mitigated relapse and attenuated bone loss, while its inhibition impeded anticipated bone growth in remodeling progress. Conclusively, we elucidated the ER stress/p-PERK/TFEB signaling orchestrated sequential mitochondria biogenesis and mitophagy under mechanical stretch, thus ensuring antioxidative capacity and osteogenic potential of cranial suture tissues.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"13 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144341084","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}

{"title":"Membrane-initiated estrogen receptor-α signaling in osteoblasts is crucial for normal regulation of the cortical bone in female mice","authors":"Yiwen Jiang, Karin Horkeby, Petra Henning, Jianyao Wu, Karin H. Nilsson, Lina Lawenius, Sofia Movérare-Skrtic, Priti Gupta, Cecilia Engdahl, Antti Koskela, Juha Tuukkanen, Lei Li, Claes Ohlsson, Marie K. Lagerquist","doi":"10.1038/s41413-025-00439-8","DOIUrl":"https://doi.org/10.1038/s41413-025-00439-8","url":null,"abstract":"<p>Membrane-initiated estrogen receptor α (mERα) signaling has been shown to affect bone mass in murine models. However, it remains unknown which cell types mediate the mERα-dependent effects on bone. In this study, we generated a novel mouse model with a conditional C451A mutation in <i>Esr1</i>, which enables selective knockout of the palmitoylation site essential for the membrane localization of ERα (C451A^f/f). First, we used <i>Runx2</i>-Cre mice to generate <i>Runx2</i>-C451A^f/f mice with conditional inactivation of mERα signaling in <i>Runx2</i>-expressing osteoblast lineage cells. No significant changes were observed in body weight, weights of estrogen-responsive organs, or serum concentrations of estradiol between female <i>Runx2</i>-C451A^f/f and homozygous C451A^f/f littermate controls. High-resolution microcomputed tomography analysis showed a consistent decrease in cortical bone mass in the tibia, femur, and vertebra L5 of <i>Runx2</i>-C451A^f/f mice and three-point bending analysis of humerus revealed an impaired mechanical bone strength in <i>Runx2</i>-C451A^f/f female mice compared to controls. Additionally, primary osteoblast cultures from mice lacking mERα signaling showed impaired differentiation compared to controls. In contrast, conditional inactivation of mERα signaling in hematopoietic cells, by transplantation of bone marrow from mice lacking mERα signaling in all cells to adult wildtype female mice, did not result in any skeletal alterations. In conclusion, this study demonstrates that mERα signaling in osteoblast lineage cells plays a crucial role in the regulation of cortical bone in female mice and shows that mERα inactivation in hematopoietic cells of adult female mice is dispensable for bone regulation.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"43 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305214","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}

{"title":"Pathophysiology of Myopenia in rheumatoid arthritis","authors":"Haiming Jin, Gang Wang, Qichen Lu, Jessica Rawlins, Junchun Chen, Saanya Kashyap, Oscar Charlesworth, Dan Xu, Lie Dai, Sipin Zhu, Jiake Xu","doi":"10.1038/s41413-025-00438-9","DOIUrl":"https://doi.org/10.1038/s41413-025-00438-9","url":null,"abstract":"<p>Rheumatoid arthritis (RA) is a prevalent and debilitating inflammatory disease that significantly impairs functional capacity and quality of life. RA accelerates musculoskeletal aging, leading to complications such as muscle degeneration and <i>sarcopenia</i>. Recent research has identified <i>myopenia</i> as a condition of significant muscle loss associated with illness, distinct from the muscle wasting seen in other chronic diseases like cancer cachexia or heart failure. In RA, <i>myopenia</i> is characterized by muscle depletion without concurrent significant fat loss, and it can affect individuals of all ages. While inflammation plays a central role, it is not the sole factor contributing to the high incidence of muscle wasting in RA. In subsequent discussions, <i>secondary sarcopenia</i> will be considered alongside <i>myopenia</i>, as both involve muscle wasting decline primarily due to disease. This review summarizes recent findings on the impact of RA-related <i>myopenia</i> and <i>secondary sarcopenia</i> on functional capacity, explores its underlying mechanisms, and discusses contemporary strategies to mitigate the process of musculoskeletal aging in RA patients.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"33 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144296123","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}

{"title":"Different role of the gut microbiota in postmenopausal and senile osteoporosis","authors":"Xuan-Qi Zheng, Zhi-Yuan Guan, Yun-Di Zhang, Chun-Li Song","doi":"10.1038/s41413-025-00432-1","DOIUrl":"https://doi.org/10.1038/s41413-025-00432-1","url":null,"abstract":"","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"116 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144278210","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}

{"title":"Chaperone-mediated autophagy directs a dual mechanism to balance premature senescence and senolysis to prevent intervertebral disc degeneration","authors":"Zhangrong Cheng, Haiyang Gao, Pengzhi Shi, Anran Zhang, Xianglong Chen, Yuhang Chen, Weikang Gan, Kangcheng Zhao, Shuai Li, Cao Yang, Yukun Zhang","doi":"10.1038/s41413-025-00441-0","DOIUrl":"https://doi.org/10.1038/s41413-025-00441-0","url":null,"abstract":"<p>Intervertebral disc degeneration (IDD) is a progressive and dynamic process in which the senescence-associated secretory phenotype (SASP) of nucleus pulposus cells (NPC) plays a significant role. While impaired chaperone-mediated autophagy (CMA) has been associated with inflammation and cellular senescence, its specific involvement in the self-perpetuating feedback loop of NPC senescence remains poorly understood. Through LAMP2A knockout in NPC, we identified a significant upregulation of DYRK1A, a core mediator of premature senescence in Down syndrome. Subsequent validation established DYRK1A as the critical driver of premature senescence in CMA-deficient NPC. Combinatorial transcription factor analysis revealed that under IL1B stimulation or CMA inhibition, elevated DYRK1A promoted FOXC1 phosphorylation and nuclear translocation, initiating transcriptional activation of cell cycle arrest. Intriguingly, CMA impairment concurrently enhanced glutamine metabolic flux in senescent NPC, thereby augmenting their survival fitness. Transcriptomic profiling demonstrated that CMA reactivation in senescent NPC facilitated fate transition from senescence to apoptosis, mediated by decreased glutamine flux via GLUL degradation. Therefore, CMA exerts protective effects against IDD by maintaining equilibrium between premature senescence and senolysis. This study elucidates CMA’s regulatory role in SASP-mediated senescence amplification circuits, providing novel therapeutic insights for IDD and other age-related pathologies.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"220 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144268826","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}