Journal of Orthopaedic Translation最新文献

{"title":"Current status and future prospects of functionalized mesenchymal stem cells for the treatment of spinal cord injury","authors":"SongTao Jin ,&nbsp;YueGang Ma ,&nbsp;SongOu Zhang","doi":"10.1016/j.jot.2026.101125","DOIUrl":"10.1016/j.jot.2026.101125","url":null,"abstract":"<div><div>Spinal cord injury (SCI) represents a critical neurological disorder characterized by intricate pathophysiological processes. The hostile local environment induced by secondary damage markedly hinders intrinsic neural repair, and currently available therapies exhibit limited clinical effectiveness. Recently, mesenchymal stem cells (MSCs) have attracted considerable attention due to their paracrine-mediated therapeutic properties, including immunoregulatory effects, neurotrophic factor secretion, and promotion of angiogenesis. Nevertheless, conventional transplantation of MSCs encounters substantial obstacles, such as poor cellular viability post-injection, inadequate homing capabilities, and diminished therapeutic outcomes in the unfavorable post-injury microenvironment. Therefore, it is essential to “functionalize” MSCs to enhance their therapeutic potential. This article systematically reviews three major MSC functionalization strategies: biomaterial-based delivery platforms, genetic engineering approaches, and drug or physical synergistic therapies. Preclinical evidence indicates that these strategies can synergistically improve motor function recovery, promote axonal regeneration and myelination, and suppress inflammatory responses. Overall, functionalized MSC therapy shows greater therapeutic promise than traditional cell transplantation. Future studies should prioritize challenges related to safety, standardization, and large-scale production to support clinical translation, and should further explore multimodal functional integration and intelligent, responsive stem cell systems to achieve breakthroughs in SCI treatment.</div></div><div><h3>The translational potential of this article</h3><div>This article presents a multidimensional therapeutic framework that integrates biomaterial-based delivery platforms, genetic engineering modifications, and non-invasive preconditioning methods to synergistically enhance the survival and functionality of transplanted cells within the hostile injury microenvironment. Preclinical evidence demonstrates these approaches effectively promote motor recovery, axonal regeneration, and inflammatory modulation, while preliminary clinical studies confirm their long-term safety and efficacy in improving neurological function. However, clinical translation faces challenges including the long-term safety of gene editing, standardization of treatment protocols, and the efficacy gap between animal models and human applications.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"58 ","pages":"Article 101125"},"PeriodicalIF":5.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147858612","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":"Targeting the glial-fibrotic scar microenvironment after spinal cord injury: From integrated protection to systematic regulation of regenerative balance","authors":"Zhaoliang Hou ,&nbsp;Shenghui Shang ,&nbsp;Haijian Sun ,&nbsp;Yixiao He ,&nbsp;Sen Guo ,&nbsp;Mingjie Sun ,&nbsp;Xiumei Tang ,&nbsp;Zhijian Wei ,&nbsp;Wenzhao Wang ,&nbsp;Bin Ning","doi":"10.1016/j.jot.2026.101120","DOIUrl":"10.1016/j.jot.2026.101120","url":null,"abstract":"<div><div>Spinal cord injury (SCI) represents a severe neurological disorder characterized by complex pathophysiological cascades, frequently resulting in irreversible sensorimotor deficits. A hallmark of this condition is the dual-phase response of glial and fibrotic scars: initially, reactive astrocytes and fibroblast-like cells form protective barriers that limit inflammatory spread and stabilize tissue integrity, yet chronically, these scars transition into inhibitory structures through excessive deposition of chondroitin sulfate proteoglycans (CSPGs) and collagen-rich extracellular matrix (ECM), obstructing axonal regeneration. Critically, these scars operate within an integrated SCI scar microenvironment, where multiple cellular, molecular, and matrix components dynamically and coordinately modulate their reparative-to-pathological shift. This review systematically examines the spatiotemporal organization, cellular heterogeneity, and molecular drivers underlying scar duality. We evaluate bidirectional interactions between glial and fibrotic components and non-scar elements. Notably, the scar microenvironment serves as a pivotal regulatory hub that dictates the switch between the protective and inhibitory phenotypes of scars post-SCI. This work underscores the scar microenvironment's centrality in SCI pathology and advances the conceptual framework for developing precision therapies to overcome neuroregenerative failure.</div><div>The Translational Potential of this Article: This review's spinal cord injury scar microenvironment theory delivers a transformative translational framework. It captures spatiotemporal crosstalk of cellular, molecular, and matrix components across injury phases, replacing fragmented single-target interventions. Representative translational strategies include artificial spinal cord ECM hydrogels, Induced Pluripotent Stem Cells (iPSCs) derived spinal cord organoid transplantation, exosome-mediated epigenetic regulation, among others, which are all aligned with pathological progression. Supported by international Phase I/II clinical trials targeting scar microenvironment components, this theory integrates basic research with clinical needs. It enables precision SCI therapy through coordinated intervention logic, accelerating the translation from symptomatic management to curative neural repair.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"58 ","pages":"Article 101120"},"PeriodicalIF":5.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147996314","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":"CEST MRI: Translational prospects for intervertebral disc degeneration – from basic research to clinical applications","authors":"Renchang Chen ,&nbsp;Hao Wang ,&nbsp;Yutong Li ,&nbsp;Gang Zhang ,&nbsp;Xin Zhang ,&nbsp;Xintian Qu ,&nbsp;Wenzhe Bai ,&nbsp;Zhichao Li ,&nbsp;Yadong Wu ,&nbsp;Songlin Liang ,&nbsp;Moji Wangchen ,&nbsp;Nianhu Li ,&nbsp;Peng Kong ,&nbsp;Xu Wei","doi":"10.1016/j.jot.2026.101131","DOIUrl":"10.1016/j.jot.2026.101131","url":null,"abstract":"<div><div>Low back pain (LBP) caused by intervertebral disc degeneration (IVDD) is characterized by metabolic and biochemical alterations within the intervertebral disc (IVD) microenvironment. Conventional magnetic resonance imaging (MRI) is limited in its ability to accurately evaluate and precisely quantify changes these small-molecule changes. Chemical exchange saturation transfer (CEST) is an emerging MRI modality that exploits exchangeable protons (such as–OH, -NH, and -NH₂ groups) within tissues. It has garnered widespread clinical attention for its ability to generate imaging contrast at the molecular level <em>in vivo</em> by targeting the exchangeable groups of specific metabolites. This review summarizes the application of CEST imaging in IVDD. We begin by comparing various IVD imaging modalities to highlight the unique advantages of CEST. Next, we outline the fundamental concepts, theoretical basis, and quantitative methods of CEST, followed by an overview of various CEST contrast agents. By correlating IVDD pathology with CEST imaging principles, we explore the modality's potential to identify key biomarkers, including glycosaminoglycan content, pH variations, microenvironmental shifts, and pain-generating IVDs. Furthermore, we discuss standardization of CEST and clinical decision system for IVDD. Finally, we analyze the current challenges facing CEST technology and evaluate its future translational prospects—particularly its integration with artificial intelligence (AI) and multimodal imaging—to highlight future research directions.</div></div><div><h3>Translational potential statement</h3><div>CEST generates specific molecular imaging contrast in tissues rich in exchangeable protons with suitable water exchange rates. It offers a distinct advantage in non-invasively quantifying <em>in vivo</em> metabolic changes within the cartilage microenvironment. However, due to existing technical bottlenecks, CEST remains largely confined to preclinical research. The future integration of CEST with AI and multimodal imaging holds the potential to overcome these limitations, enabling the precise evaluation and prediction of degenerative diseases such as IVDD and osteoarthritis. This will drive a fundamental leap in CEST MRI assessment, transitioning from macroscopic 'structure and composition' to microscopic \"molecular concentration and chemical environment\" analysis and \"intelligent prediction\". Such advancements will not only provide robust molecular imaging evidence for ultra-early diagnosis and precision targeted therapy but also establish CEST as an irreplaceable tool in the future of precision medicine and intelligent imaging diagnostics.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"58 ","pages":"Article 101131"},"PeriodicalIF":5.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148178197","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":"Quantification of skeletal muscle density, mass and fat fraction using single-energy computed tomography","authors":"Jonathan Bammessel ,&nbsp;Stefan Bartenschlager ,&nbsp;Oliver Chaudry ,&nbsp;Nicolai Krekiehn ,&nbsp;Fjola Johannesdottir ,&nbsp;Ling Wang ,&nbsp;Michael Uder ,&nbsp;Georg Schett ,&nbsp;Klaus Engelke","doi":"10.1016/j.jot.2026.101094","DOIUrl":"10.1016/j.jot.2026.101094","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Currently, CT muscle density is measured in Hounsfield units and is not converted to g/cm&lt;sup&gt;3&lt;/sup&gt;. Muscle mass and fat fraction (FF) cannot be measured from CT images.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;We propose a phantomless calibration method to calculate muscle tissue and muscle density in g/cm&lt;sup&gt;3&lt;/sup&gt;, as well as muscle FF in percent, based on the measurement of water-offset corrected CT values of muscle and subcutaneous adipose tissue (SAT). Calibration requires the mass density and FF of standard muscle tissue (SMT), as well as the FF of SAT. In this study, the International Commission on Radiation Units (ICRU) definition of muscle tissue with a mass density of 1.05 g/cm&lt;sup&gt;3&lt;/sup&gt; was used as standard muscle tissue (SMT). The CT values of SMT were measured using a phantom scanned with seven different CT scanners employing tube voltages ranging from 80 to 140 kV. Existing CT scans of 42 men aged 72 years or over were used to estimate the accuracy errors of the calibrated parameters of the paraspinal muscles. MR Dixon data from 31 subjects were available for comparing CT and MRI FF.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;The mean SMT CT value of the phantom measurements was 47.7 ± 1.9 HU. In line with previous publications, the SMT fat fraction was set to 3%, and the subcutaneous adipose tissue (SAT) FF to 85%. Using an SMT CT value of 48 HU, the mean muscle tissue density, muscle density, and muscle fat fraction (FF) of the 41 subjects were 0.94 ± 0.08 g/cm&lt;sup&gt;3&lt;/sup&gt;, 1.04 ± 0.01 g/cm&lt;sup&gt;3&lt;/sup&gt;, and 11.7 ± 6.4%, respectively. Simulated variations in SMT density of ±0.02 g/cm&lt;sup&gt;3&lt;/sup&gt;, SMT CT value of ±2 HU, SMT FF of 5%, and SAT FF of ±3 HU resulted in relative changes in muscle and muscle tissue densities and in absolute changes in muscle FF of below 5%. Simulated accuracy errors were comparable to those caused by an error of ±5 HU in the water offset corrections of the measured CT values of muscle and SAT. The mean MRI fat fraction values were 4.1% higher than the mean CT FF values. The two measurements exhibited a high degree of linear correlation (r&lt;sup&gt;2&lt;/sup&gt; = 0.88, p &lt; 0.001).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;The proposed methodology for muscle calibration in single-energy CT images showed a high degree of agreement with MR Dixon FF measurements. The simulated accuracy errors were comparable to those caused by missing water offset corrections of the measured CT values. This is a proof-of-concept study, further validation in subjects with higher muscle FF and in other muscle groups is required.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;The translational potential of this article&lt;/h3&gt;&lt;div&gt;Quantitative assessments of muscle properties such as density and fat infiltration are important biomarkers for myopathies, sarcopenia, obesity and potentially for osteoporosis. While MRI techniques are state-of-the-art, the opportunistic use of existing CT scans can support screening strategies and may help to ide","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"58 ","pages":"Article 101094"},"PeriodicalIF":5.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147858611","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":"Txnip regulates glycolysis and tricarboxylic acid cycle balance to maintain bone homeostasis","authors":"Xiankun Cao ,&nbsp;Kexin Liu ,&nbsp;Kewei Rong ,&nbsp;Bin Pan ,&nbsp;Hang Zhang ,&nbsp;Hanwen Chang ,&nbsp;Yin Li ,&nbsp;Xiao Yang ,&nbsp;Shaotian Fu ,&nbsp;Jie Zhao ,&nbsp;Yaokai Gan ,&nbsp;Hui Ma ,&nbsp;An Qin","doi":"10.1016/j.jot.2026.101095","DOIUrl":"10.1016/j.jot.2026.101095","url":null,"abstract":"<div><h3>Background</h3><div>Bone remodeling and energy metabolism are closely linked in mammals. Maintaining a balanced glycolysis and tricarboxylic acid (TCA) cycle ratio is essential for bone remodeling. Therefore, it was of great interest to reveal key regulators in bone remodeling under different glucose metabolic states.</div></div><div><h3>Methods</h3><div>We created genetic knockout mice for Thioredoxin-interacting protein (<em>Txnip</em>) in bone marrow-derived macrophages (BMMs) and mesenchymal stromal cells (BMSCs), followed by bone histomorphometry and histological analysis. Metabolic regulation mechanisms were investigated using Seahorse and ¹³C-Glucose tracer metabolic flux experiments. KAN0438757-specific 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (pfkfb3) inhibitor was selected for rescue experiments.</div></div><div><h3>Results</h3><div><em>Txnip</em> knockout led to increased anaerobic glycolysis and disrupted the TCA cycle, thereby inhibiting osteoclast formation. Knockout of <em>Txnip</em>, which enhanced that enhanced glycolysis also damaged osteoblast differentiation due to impaired TCA cycle. Elevated Txnip levels were observed in aged human bone marrow derived mesenchymal stem cells (BMSCs) and mice BMSCs. <em>Txnip</em> upregulation blocked glucose influx and impaired subsequent glycolysis and TCA cycle, resulting in impaired bone formation. Reduced osteoblast differentiation is correlated with delayed fracture healing during BMSCs-enrichment therapy in aged patients.</div></div><div><h3>Conclusions</h3><div><em>Txnip</em> is essential for balanced glycolysis and TCA cycle. Either extremely low or extremely high expression of Txnip will disrupt this balance and thus impair bone homeostasis.</div></div><div><h3>The translational potential of this article</h3><div>Elevated Txnip levels in senescent human BMSCs correlate with delayed fracture healing during aging. The Txnip inhibition for rebuilding balanced glycolysis and the TCA cycle has great clinical translation potential in autologous BMSCs-enrichment therapy in aged patients.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"58 ","pages":"Article 101095"},"PeriodicalIF":5.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147858613","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":"Talin1 loss activates DRG neurons to accelerate bone remodeling and fracture healing in mice","authors":"Qinnan Yan ,&nbsp;Donghao Gan ,&nbsp;Kangtai Xu ,&nbsp;Zecai Chen ,&nbsp;Sixiong Lin ,&nbsp;Bo Zhou ,&nbsp;Zhen Xu ,&nbsp;Qiyue Zhong ,&nbsp;Chu Tao ,&nbsp;Yiming Zhong ,&nbsp;Shaochuan Huo ,&nbsp;Weihong Yi ,&nbsp;Zilong Wang ,&nbsp;Xuejun Song ,&nbsp;Lei Qin ,&nbsp;Guozhi Xiao","doi":"10.1016/j.jot.2026.101113","DOIUrl":"10.1016/j.jot.2026.101113","url":null,"abstract":"<div><h3>Background</h3><div>Bone tissue is densely innervated by sensory nerve fibers, whose roles in bone remodeling and regeneration are poorly defined. This study aims to investigate the physiological function of Talin1, a key focal adhesion protein, in dorsal root ganglion (DRG) neurons in pain processing and its specific impact on bone remodeling and fracture healing.</div></div><div><h3>Materials and methods</h3><div>We utilized a transgenic mouse model (<em>Advillin-Cre</em>^{<em>ERT2</em>}<em>; Talin1</em>^{<em>fl/fl</em>}) to delete Talin1 expression in sensory neurons under tamoxifen induction. Pain sensitivity, bone mass, and fracture healing were evaluated in adult mice. Transcriptomic analysis, immunofluorescence, western blot, scanning and transmission electron microscopy, alongside a highly localized pharmacological inhibition model using BIBN-loaded hydrogels, were employed to delineate the underlying mechanisms.</div></div><div><h3>Results</h3><div>Talin1 is predominantly expressed in C-fiber DRG neurons and its expression is significantly downregulated following bone fracture. Talin1 loss markedly activates DRG sensory neurons and increases mechanical, but not thermal, pain sensitivity in mice. Concurrently, Talin1 deficiency inhibits mitophagy and impairs mitochondrial function, as indicated by altered mitochondrial morphology, abnormal reactive oxygen species production and reduced mitochondrial membrane potential. Furthermore, beyond its role in nociception, Talin1 loss not only increases bone mass in both adult and aged mice but also accelerates fracture healing by modulating bone remodeling. This pro-healing phenotype coincides with increased expression of calcitonin gene-related peptide (CGRP) in DRG neurons. Critically, pharmacological inhibition of CGRP receptors at the fracture site by BIBN abolishes the fracture healing-promoting effect caused by Talin1 loss.</div></div><div><h3>Conclusions</h3><div>Our studies demonstrate that Talin1 plays a pivotal role in modulating sensory neuron activation, pain perception, and bone remodeling. Specifically, Talin1 loss accelerates bone repair by upregulating CGRP, thereby establishing a Talin1-CGRP signaling axis that mediates sensory neuron control of fracture healing.</div></div><div><h3>The translational potential of this article</h3><div>This research highlights the dual role of Talin1 in sensory neurons in modulating both pain perception and bone remodeling, and emphasizes the potential for targeting Talin1 signaling as a therapeutic strategy to alleviate pain or to accelerate fracture healing.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"58 ","pages":"Article 101113"},"PeriodicalIF":5.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147858683","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":"Telomerase reverse transcriptase mediates bone formation for osteoporosis via activating BMP4/Smad1 pathway","authors":"Jinjin Ma ,&nbsp;Xiaonan Yuan ,&nbsp;Yao Xiao ,&nbsp;Huan Wang ,&nbsp;Youzhi Hong ,&nbsp;Yang Zhang ,&nbsp;Yuan Chen ,&nbsp;Houfeng Zheng ,&nbsp;Jiaying Li ,&nbsp;Bin Li","doi":"10.1016/j.jot.2026.101116","DOIUrl":"10.1016/j.jot.2026.101116","url":null,"abstract":"<div><h3>Background</h3><div>The role of telomerase reverse transcriptase (TERT) in bone metabolism remains poorly defined. This study investigates its function in osteoporosis (OP) pathogenesis and its therapeutic potential.</div></div><div><h3>Methods</h3><div>TERT expression was analyzed in clinical OP specimens and ovariectomized (OVX) mice. Mechanisms were probed using RNA-seq, gain/loss-of-function studies, and pathway inhibition. Exosomes derived from TERT-overexpressing BMSCs (TERT-Exo) were functionalized with a bone-targeting aptamer (Apt-TERT-Exo) and evaluated in OVX mice.</div></div><div><h3>Results</h3><div>TERT was downregulated in OP, correlating with impaired osteogenesis. TERT was identified as a novel upstream activator of the BMP4/Smad1 pathway, essential for its pro-osteogenic effect. Apt-TERT-Exo exhibited enhanced bone accumulation and systemic administration effectively restored trabecular bone mass in OVX mice by promoting BMSC osteogenesis.</div></div><div><h3>Conclusion</h3><div>TERT is a novel upstream regulator of osteogenesis via BMP4/Smad1. The Apt-TERT-Exo platform represents a promising targeted, cell-free therapeutic approach for osteoporosis.</div></div><div><h3>The translational potential statement</h3><div>The Translational Potential of this Article.The Apt-TERT-Exo platform presents a targeted, cell-free strategy for osteoanabolic therapy. Its design addresses key translational challenges by enabling precise delivery to bone tissue, potentially minimizing systemic side effects and offering a promising new avenue for treating osteoporosis.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"58 ","pages":"Article 101116"},"PeriodicalIF":5.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147858685","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":"From undruggable to degradable: A deep learning-enabled framework for precision orthopaedic protein degradation","authors":"Lulu Zhang ,&nbsp;Yan Wang ,&nbsp;Dong Wang ,&nbsp;Jianxiong Ma","doi":"10.1016/j.jot.2026.101118","DOIUrl":"10.1016/j.jot.2026.101118","url":null,"abstract":"<div><h3>Background/objective</h3><div>A fundamental translational impasse in musculoskeletal disorders—from osteoarthritis to bone metastases—is the “undruggability” of critical pathological drivers sequestered within anatomically restricted and avascular skeletal niches. While Targeted Protein Degradation (TPD) offers a revolutionary event-driven modality to eradicate these refractory targets, its clinical translation to orthopaedics is severely hindered by the physicochemical incompatibility of large degraders with dense extracellular matrices and the scarcity of bone-specific E3 ligases.</div></div><div><h3>Methods</h3><div>In this review, we present a transformative framework integrating deep learning (DL) with multimodal omics to circumvent these barriers. We systematically examine how emerging DL architectures—spanning geometric deep learning, protein language models, and generative design—are redefining the orthopaedic TPD pipeline.</div></div><div><h3>Results</h3><div>We highlight computational strategies for prioritizing cryptic pockets on “undruggable” skeletal transcription factors, identifying tissue-restricted E3 ligases via single-cell transcriptomics to minimize systemic toxicity, and optimizing degrader permeability (“penetrability-first” design) to navigate dense cartilage and bone matrices.</div></div><div><h3>Conclusion</h3><div>By bridging the gap between computational prediction and skeletal pathobiology, this roadmap outlines a shift in orthopaedic care from palliative symptom management to precise, mechanism-based microenvironmental reprogramming.</div></div><div><h3>The Translational Potential of this Article</h3><div>This review provides a timely, computationally-driven roadmap to translate Targeted Protein Degradation (TPD) from oncology to orthopaedics. By integrating deep learning with skeletal pathobiology to overcome matrix penetrability and off-target toxicity, this framework accelerates the development of precision degraders. Ultimately, it offers a tangible strategy to shift the clinical management of joint degeneration, osteoporosis, and bone tumors from palliative care to durable, mechanism-based microenvironmental reprogramming.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"58 ","pages":"Article 101118"},"PeriodicalIF":5.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147951592","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":"Deer antler polypeptides promote osteogenesis for fracture healing via activating neurosensory PGE2/EP4/p-CREB axis","authors":"Yunfan He ,&nbsp;Jihao Xi ,&nbsp;Haoqiang Dai ,&nbsp;Liang Fang ,&nbsp;Yihe Yu ,&nbsp;Yonggan Ying ,&nbsp;Jin Li ,&nbsp;Danqing Fu ,&nbsp;Chenjie Xia","doi":"10.1016/j.jot.2026.101112","DOIUrl":"10.1016/j.jot.2026.101112","url":null,"abstract":"<div><h3>Background</h3><div>Deer antler polypeptides (DAPs), one of the most bioactive components of deer antler, have been reported to possess multiple biological functions. However, the role of DAPs in fracture healing remains unclear. This study aims to investigate the therapeutic effects of DAPs on fracture healing and elucidate their potential pharmacological mechanism.</div></div><div><h3>Methods</h3><div>LC-MS/MS was employed to analyze the peptide compositions and serum metabolites of DAPs. Sensory nerve-specific EP4 receptor knockout (<em>EP4</em>^{<em>Avil</em>}) mice, sensory nerve- and skeletal stem/progenitor cells-specific fluorescence reporter mice were subjected to a transverse tibial fracture followed by oral administration of DAPs at 50 mg/kg/day. <em>In vitro</em>, primary bone marrow cells (BMCs) were incubated with serum containing DAPs, and dorsal root ganglion (DRG) neurons were subsequently treated with the conditioned medium harvested from these BMCs. A series of experimental approaches including gait analysis, μCT, three-point bending test, calcein double-labeling staining, IHC, IF, ELISA, qRT-PCR and western blotting were performed on both <em>in vivo</em> and <em>in vitro</em> models.</div></div><div><h3>Results</h3><div>LC-MS/MS analysis identified 303 functional peptides and 32 differential metabolites. DAPs substantially accelerated mouse fracture healing by enhancing callus formation. PGE2 production was significantly increased in the fracture callus of DAPs-treated mice and in BMCs stimulated with DAPs-containing serum, which activated the EP4 receptor in sensory nerves and DRG neurons <em>in vivo</em> and <em>in vtiro</em>. This activation consequently improved hypothalamic CREB phosphorylation and diminished sympathetic tone, thereby promoting the osteogenic differentiation of SSPCs. However, DAPs-mediated osteogenesis in the fracture callus was abolished in <em>EP4</em>^{<em>Avil</em>} mice due to the blockade of neurosensory PGE2/EP4/p-CREB signaling.</div></div><div><h3>Conclusion</h3><div>This study demonstrate that DAPs enhance fracture healing by promoting osteogenesis via neurosensory PGE2/EP4/p-CREB axis.</div></div><div><h3>The Translational Potential of this Article</h3><div>Deer antler polypeptides (DAPs) are the primary bioactive components of deer antler, a self‑regenerative mammalian organ. This study reveals that DAPs can promote fracture healing in mice through activation of the neurosensory PGE2/EP4/p‑CREB axis. These findings provide a novel bioactive candidate for enhancing bone repair, which holds translational potential for developing therapeutics to treat fractures or other bone defects in clinical practice”. at the end of the abstract as it should be included as part of the abstract.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"58 ","pages":"Article 101112"},"PeriodicalIF":5.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147858684","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":"Re-innervation of neuromuscular junctions by a conductive polypyrrole/silk fibroin/GelMA hydrogel facilitated functional skeletal muscle regeneration following volumetric muscle loss","authors":"Dimulati Maimaiti ,&nbsp;Ziying He ,&nbsp;Jinuo Liu ,&nbsp;Shihan Gao ,&nbsp;Guanyu Yang ,&nbsp;Ce Qi ,&nbsp;Kai Meng ,&nbsp;Fan He ,&nbsp;Huijing Zhao ,&nbsp;Xi Chen","doi":"10.1016/j.jot.2026.101128","DOIUrl":"10.1016/j.jot.2026.101128","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Introduction&lt;/h3&gt;&lt;div&gt;Volumetric muscle loss (VML) is a significant clinical challenge that severely compromises patients' motor function and often results in irreversible disability. While conventional hydrogels have been explored for VML repair, their inability to address peripheral nerve denervation has limited functional recovery.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Objectives&lt;/h3&gt;&lt;div&gt;The objective of this study was to develop a conductive double-crosslinking hydrogel (PPY@SF/GelMA) by integrating polypyrrole (PPY) into gelatin methacryloyl (GelMA) and silk fibroin (SF), aiming to simultaneously promote myotube formation and nerve re-innervation.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;The micro-architecture, compressive strength, rheological properties, swelling behavior, and conductivity of the PPY@SF/GelMA hydrogel were assessed. The influence of the conductive hydrogel on &lt;em&gt;in vitro&lt;/em&gt; myogenic differentiation of C2C12 myoblast cells and angiogenic differentiation of endothelial cells was evaluated. The &lt;em&gt;in vivo&lt;/em&gt; biodegradation and biocompatibility of the conductive hydrogel were assessed through subcutaneous implantation in the dorsal region of C57BL mice. The regenerative potential of the conductive hydrogel for skeletal muscle and peripheral nerve repair was investigated using a mouse tibialis anterior VML model.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Compared to pure GelMA or SF hydrogels, the PPY@SF/GelMA composite exhibited superior mechanical resilience, tunable swelling kinetics, exceptional biocompatibility, and enhanced electrical conductivity. &lt;em&gt;In vitro&lt;/em&gt; experiments using C2C12 murine myoblasts demonstrated that the PPY@SF/GelMA hydrogel markedly upregulated myogenic differentiation markers (e.g., &lt;em&gt;Mhc&lt;/em&gt;, &lt;em&gt;Myog&lt;/em&gt;, and &lt;em&gt;MyoD&lt;/em&gt;) and promoted the formation of multinucleated myotubes. Additionally, the conductive hydrogel exhibited pro-angiogenic potential by enhancing endothelial cell differentiation, as evidenced by new formation of endothelial tubes. &lt;em&gt;In vivo&lt;/em&gt;, histopathological analysis showed no signs of toxicity from the implanted conductive hydrogel. PPY@SF/GelMA implantation facilitated the regeneration of aligned muscle fibers, reduced fibrotic collagen deposition, and accelerated neovascularization. Importantly, the conductive hydrogel successfully promoted peripheral nerve re-innervation by restoring neuromuscular junctions. RNA-seq analysis further revealed the involvement of the phosphoinositide 3-kinase (PI3K) signaling pathway in the newly regenerated muscle treated with PPY@SF/GelMA.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Our findings demonstrate PPY@SF/GelMA as a promising therapeutic scaffold to facilitate both myogenic and neurogenic regeneration after VML injuries, offering a translatable strategy for complex musculoskeletal repair.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;The translational potential of this article&lt;/h3&gt;&lt;div&gt;The failure of skeletal muscle regeneration following VML injuries is prima","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"58 ","pages":"Article 101128"},"PeriodicalIF":5.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147951586","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}