Journal of Bone and Mineral Research最新文献

{"title":"Isolation and characterization of bone mesenchymal cell small extracellular vesicles using a novel mouse model.","authors":"David G Monroe, Naureen Javeed, Jennifer L Rowsey, Ming Ruan, Chantal E McCabe, Bryan T Piatkowski, Abhishek Roy, Madhusudhan R Bobbili, Johannes Grillari, Sundeep Khosla","doi":"10.1093/jbmr/zjae135","DOIUrl":"10.1093/jbmr/zjae135","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) are key mediators of cell-cell communication and are involved in transferring specific biomolecular cargo to recipient cells to regulate their physiological functions. A major challenge in the understanding of EV function in vivo is the difficulty ascertaining the origin of the EV particles. The recent development of the \"Snorkel-tag,\" which includes EV-membrane-targeted CD81 fused to a series of extra-vesicular protein tags, can be used to mark EVs originating from a specific source for subsequent isolation and characterization. We developed an in vivo mouse model, termed \"CAGS-Snorkel,\" which expresses the Snorkel-tag under the control of the Cre-lox system, and crossed this mouse with either Prx1-Cre (mesenchymal progenitors) or Ocn-Cre (osteoblasts/osteocytes) and isolated Snorkel-tagged EVs from the mouse bone marrow plasma using a magnetic bead affinity column. miRNA-sequencing was performed on the isolated EVs, and although similar profiles were observed, a few key miRNAs involved in bone metabolism (miR-106b-5p, miRs-19b-3p, and miRs-219a-5p) were enriched in the Ocn-derived relative to the Prx1-derived EV subpopulations. To characterize the effects of these small EVs on a bone cell target, cultured mouse bone marrow stromal cells were treated with Prx1 or Ocn EVs, and mRNA-sequencing was performed. Pathways involved in ossification, bone development, and extracellular matrix interactions were regulated by both EV subpopulations, whereas a few pathways including advanced glycation end-products signaling were uniquely regulated in the Ocn EV subpopulation, underlying important biological effects of specific EV subpopulations within the bone marrow microenvironment. These data demonstrate that EV isolation in vivo using the CAGS-Snorkel mouse model is a useful tool in characterizing the cargo and understanding the biology of tissue-specific EVs. Moreover, while bone mesenchymal cell populations share a common EV secretory profile, we uncover key differences based on the stage of osteoblastic differentiation that may have important biological consequences.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"1633-1643"},"PeriodicalIF":5.1,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11523127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142034709","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":"The G protein-coupled receptor ADGRG6 maintains mouse growth plate homeostasis through IHH signaling.","authors":"Fangzhou Bian, Victoria Hansen, Hong Colleen Feng, Jingyu He, Yanshi Chen, Kaining Feng, Brenda Ebrahimi, Ryan S Gray, Yang Chai, Chia-Lung Wu, Zhaoyang Liu","doi":"10.1093/jbmr/zjae144","DOIUrl":"10.1093/jbmr/zjae144","url":null,"abstract":"<p><p>The cartilage growth plate is essential for maintaining skeletal growth; however, the mechanisms governing postnatal growth plate homeostasis are still poorly understood. Using approaches of molecular mouse genetics and spatial transcriptomics applied to formalin-fixed, paraffin-embedded tissues, we show that ADGRG6/GPR126, a cartilage-enriched adhesion G protein-coupled receptor (GPCR), is essential for maintaining slow-cycling resting zone cells, appropriate chondrocyte proliferation and differentiation, and growth plate homeostasis in mice. Constitutive ablation of Adgrg6 in osteochondral progenitor cells with Col2a1Cre leads to a shortened resting zone, formation of cell clusters within the proliferative zone, and an elongated hypertrophic growth plate, marked by limited expression of parathyroid hormone-related protein (PTHrP) but increased Indian Hedgehog (IHH) signaling throughout the growth plate. Attenuation of smoothened-dependent hedgehog signaling restored the Adgrg6 deficiency-induced expansion of hypertrophic chondrocytes, confirming that IHH signaling can promote chondrocyte hypertrophy in a PTHrP-independent manner. In contrast, postnatal ablation of Adgrg6 in mature chondrocytes with AcanCreERT2, induced after the formation of the resting zone, does not affect PTHrP expression but causes an overall reduction of growth plate thickness marked by increased cell death specifically in the resting zone cells and a general reduction of chondrocyte proliferation and differentiation. Spatial transcriptomics reveals that ADGRG6 is essential for maintaining chondrocyte homeostasis by regulating osteogenic and catabolic genes in all the zones of the postnatal growth plates, potentially through positive regulation of SOX9 expression. Our findings elucidate the essential role of a cartilage-enriched adhesion GPCR in regulating cell proliferation and hypertrophic differentiation by regulation of PTHrP/IHH signaling, maintenance of slow-cycle resting zone chondrocytes, and safeguarding chondrocyte homeostasis in postnatal mouse growth plates.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"1644-1658"},"PeriodicalIF":5.1,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11523133/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142138795","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":"The CAGS-Snorkel mouse: a game changer in the identification of extracellular vesicles originating from cells of the osteogenic lineage.","authors":"Colin Farquharson","doi":"10.1093/jbmr/zjae155","DOIUrl":"10.1093/jbmr/zjae155","url":null,"abstract":"","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"1521-1522"},"PeriodicalIF":5.1,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337966","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":"A quasi-experimental study about shared decision-making and motivational interviewing on patients with a recent fracture attending Fracture Liaison Services.","authors":"Lieke Maas, Mickaël Hiligsmann, Caroline E Wyers, Sandrine Bours, Trudy van der Weijden, Joop P van den Bergh, Marsha van Oostwaard, Sander M J van Kuijk, Annelies Boonen","doi":"10.1093/jbmr/zjae161","DOIUrl":"10.1093/jbmr/zjae161","url":null,"abstract":"<p><p>Shared decision-making (SDM) aims to improve patients' experiences with care, treatment adherence, and health outcomes. However, the effectiveness of SDM in patients with a recent fracture who require anti-osteoporosis medication (AOM) is unclear. The objective of this study was to assess the effectiveness of a multicomponent adherence intervention (MCAI) including a patient decision aid (PDA) and motivational interviewing at Fracture Liaison Services (FLS) on multiple outcomes compared with usual care (UC). This pre-post superiority study included patients with a recent fracture attending FLS and with AOM treatment indication. The primary outcome was 1-year AOM persistence measured by pharmacy records. Secondary outcomes included treatment initiation, AOM adherence (measured by medication possession ratio [MPR]), decision quality (SDM process; 0-100, best), and decisional conflict (0-100, highest conflict), subsequent fractures, and mortality. Outcomes were tested in MCAI and UC groups at the first FLS visit and 4 and 12 months afterwards. Multiple imputation and uni- and multivariable analyses were performed. Post hoc analyses assessed the role of health literacy level. In total, 245 patients (MCAI: n = 136, UC: n = 109) were included. AOM persistence was 80.4% in the MCAI and 76.7% in the UC group (p=.626). SDM process scores were significantly better in MCAI (60.4 vs 55.1; p = .003). AOM initiation (97.8% vs 97.5%), MPR (90.9% vs 88.3%, p=.582), and decisional conflict (21.7 vs 23.0; p = .314) did not differ between groups. Results did not change importantly after adjustment. Stratified analyses by health literacy showed a better effect on MPR and SDM in those with adequate health literacy. This study showed no significant effect on AOM persistence; however, it demonstrated a significant positive effect of MCAI on SDM process in FLS attendees. (Netherlands Trial Registry, Trial NL7236 [NTR7435]; version 1.0; 26-11-2020 https://onderzoekmetmensen.nl/nl/trial/22858).</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"1584-1595"},"PeriodicalIF":5.1,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11523095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337959","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":"Use of race and ethnicity in fracture risk assessment: it is time for re-assessment.","authors":"Marcella D Walker, John P Bilezikian","doi":"10.1093/jbmr/zjae153","DOIUrl":"10.1093/jbmr/zjae153","url":null,"abstract":"","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"1519-1520"},"PeriodicalIF":5.1,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337967","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":"Development and reporting of artificial intelligence in osteoporosis management.","authors":"Guillaume Gatineau, Enisa Shevroja, Colin Vendrami, Elena Gonzalez-Rodriguez, William D Leslie, Olivier Lamy, Didier Hans","doi":"10.1093/jbmr/zjae131","DOIUrl":"10.1093/jbmr/zjae131","url":null,"abstract":"<p><p>An abundance of medical data and enhanced computational power have led to a surge in artificial intelligence (AI) applications. Published studies involving AI in bone and osteoporosis research have increased exponentially, raising the need for transparent model development and reporting strategies. This review offers a comprehensive overview and systematic quality assessment of AI articles in osteoporosis while highlighting recent advancements. A systematic search in the PubMed database, from December 17, 2020 to February 1, 2023 was conducted to identify AI articles that relate to osteoporosis. The quality assessment of the studies relied on the systematic evaluation of 12 quality items derived from the minimum information about clinical artificial intelligence modeling checklist. The systematic search yielded 97 articles that fell into 5 areas; bone properties assessment (11 articles), osteoporosis classification (26 articles), fracture detection/classification (25 articles), risk prediction (24 articles), and bone segmentation (11 articles). The average quality score for each study area was 8.9 (range: 7-11) for bone properties assessment, 7.8 (range: 5-11) for osteoporosis classification, 8.4 (range: 7-11) for fracture detection, 7.6 (range: 4-11) for risk prediction, and 9.0 (range: 6-11) for bone segmentation. A sixth area, AI-driven clinical decision support, identified the studies from the 5 preceding areas that aimed to improve clinician efficiency, diagnostic accuracy, and patient outcomes through AI-driven models and opportunistic screening by automating or assisting with specific clinical tasks in complex scenarios. The current work highlights disparities in study quality and a lack of standardized reporting practices. Despite these limitations, a wide range of models and examination strategies have shown promising outcomes to aid in the earlier diagnosis and improve clinical decision-making. Through careful consideration of sources of bias in model performance assessment, the field can build confidence in AI-based approaches, ultimately leading to improved clinical workflows and patient outcomes.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"1553-1573"},"PeriodicalIF":5.1,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11523092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142007920","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":"Inactivation of spermine synthase in mice causes osteopenia due to reduced osteoblast activity.","authors":"Timur A Yorgan, Yihao Zhu, Philip Wiedemann, Kenneth Schöneck, Sandra Pohl, Michaela Schweizer, Michael Amling, Florian Barvencik, Ralf Oheim, Thorsten Schinke","doi":"10.1093/jbmr/zjae156","DOIUrl":"10.1093/jbmr/zjae156","url":null,"abstract":"<p><p>Spermine synthase, encoded by the SMS gene, is involved in polyamine metabolism, as it is required for the synthesis of spermine from its precursor molecule spermidine. Pathogenic variants of SMS are known to cause Snyder-Robinson syndrome (SRS), an X-linked recessive disorder causing various symptoms, including intellectual disability, muscular hypotonia, infertility, but also skeletal abnormalities, such as facial dysmorphisms and osteoporosis. Since the impact of a murine SMS deficiency has so far only been analyzed in Gy mice, where a large genomic deletion also includes the neighboring Phex gene, there is only limited knowledge about the potential role of SMS in bone cell regulation. In the present manuscript, we describe 2 patients carrying distinct SMS variants, both diagnosed with osteoporosis. Whereas the first patient displayed all characteristic hallmarks of SRS, the second patient was initially diagnosed, based on laboratory findings, as a case of adult-onset hypophosphatasia. To study the impact of SMS inactivation on bone remodeling, we took advantage of a newly developed mouse model carrying a pathogenic SMS variant (p.G56S). Compared to their wildtype littermates, 12-wk-old male SMSG56S/0 mice displayed reduced trabecular bone mass and cortical thickness, as assessed by μCT analysis of the femur. This phenotype was histologically confirmed by the analysis of spine and tibia sections, where we also observed a moderate enrichment of non-mineralized osteoid in SMSG56S/0 mice. Cellular and dynamic histomorphometry further identified a reduced bone formation rate as a main cause of the low bone mass phenotype. Likewise, primary bone marrow cells from SMSG56S/0 mice displayed reduced capacity to form a mineralized matrix ex vivo, thereby suggesting a cell-autonomous mechanism. Taken together, our data identify SMS as an enzyme with physiological relevance for osteoblast activity, thereby demonstrating an important role of polyamine metabolism in the control of bone remodeling.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"1606-1620"},"PeriodicalIF":5.1,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337963","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":"Microbiome-induced increases and decreases in bone matrix strength can be initiated after skeletal maturity.","authors":"Chongshan Liu, Erika L Cyphert, Samuel J Stephen, Bowen Wang, Angie L Morales, Jacob C Nixon, Nicholas R Natsoulas, Matthew Garcia, Pablo Blazquez Carmona, Albert C Vill, Eve Donnelly, Ilana L Brito, Deepak Vashishth, Christopher J Hernandez","doi":"10.1093/jbmr/zjae157","DOIUrl":"10.1093/jbmr/zjae157","url":null,"abstract":"<p><p>Recent studies in mice have indicated that the gut microbiome can regulate bone tissue strength. However, prior work involved modifications to the gut microbiome in growing animals and it is unclear if the same changes in the microbiome, applied later in life, would change matrix strength. Here we changed the composition of the gut microbiome before and/or after skeletal maturity (16 weeks of age) using oral antibiotics (ampicillin + neomycin). Male and female mice (n = 143 total, n = 12-17/group/sex) were allocated into five study groups: (1) Unaltered, (2) Continuous (dosing 4-24 weeks of age), (3) Delayed (dosing only 16-24 weeks of age), (4) Initial (dosing 4-16 weeks of age, suspended at 16 weeks), and (5) Reconstituted (dosing from 4-16 weeks following by fecal microbiota transplant from Unaltered donors). Animals were euthanized at 24 weeks of age. In males, bone matrix strength in the femur was 25%-35% less than expected by geometry in mice from the Continuous (p = 0.001), Delayed (p = 0.005), and Initial (p = 0.040) groups as compared to Unaltered. Reconstitution of the gut microbiota led to a bone matrix strength similar to Unaltered animals (p = 0.929). In females, microbiome-induced changes in bone matrix strength followed the same trend as males but were not significantly different, demonstrating a sex-dependent response of bone matrix to the gut microbiota. Minor differences in chemical composition of bone matrix were observed with Raman spectroscopy. Our findings indicate that microbiome-induced impairment of bone matrix in males can be initiated and/or reversed after skeletal maturity. The portion of the femoral cortical bone formed after skeletal maturity (16 weeks) was small; suggesting that microbiome-induced changes in bone matrix occurred without osteoblast/osteoclast turnover through a yet unidentified mechanism. These findings provide evidence that the mechanical properties of bone matrix can be altered in the adult skeleton.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"1621-1632"},"PeriodicalIF":5.1,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11523134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337964","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":"Short-term risk of fracture is increased by deficits in cortical and trabecular bone microarchitecture independent of DXA BMD and FRAX: Bone Microarchitecture International Consortium (BoMIC) prospective cohorts.","authors":"Marine Sarfati, Roland Chapurlat, Alyssa B Dufour, Elisabeth Sornay-Rendu, Blandine Merle, Steven K Boyd, Danielle E Whittier, David A Hanley, David Goltzman, Pawel Szulc, Andy Kin On Wong, Eric Lespessailles, Sundeep Khosla, Serge Ferrari, Emmanuel Biver, Claes Ohlsson, Mattias Lorentzon, Dan Mellström, Maria Nethander, Elizabeth J Samelson, Douglas P Kiel, Marian T Hannan, Mary L Bouxsein","doi":"10.1093/jbmr/zjae143","DOIUrl":"10.1093/jbmr/zjae143","url":null,"abstract":"<p><p>Identifying individuals at risk for short-term fracture is essential to offer prompt beneficial treatment, especially since many fractures occur in those without osteoporosis by DXA-aBMD. We evaluated whether deficits in bone microarchitecture and density predict short-term fracture risk independent of the clinical predictors, DXA-BMD and FRAX. We combined data from eight cohorts to conduct a prospective study of bone microarchitecture at the distal radius and tibia (by HR-pQCT) and 2-year incidence of fracture (non-traumatic and traumatic) in 7327 individuals (4824 women, 2503 men, mean 69 ± 9 years). We estimated sex-specific hazard ratios (HR) for associations between bone measures and 2-year fracture incidence, adjusted for age, cohort, height, and weight, and then additionally adjusted for FN aBMD or FRAX for major osteoporotic fracture. Only 7% of study participants had FN T-score ≤ -2.5, whereas 53% had T-scores between -1.0 and -2.5 and 37% had T-scores ≥-1.0. Two-year cumulative fracture incidence was 4% (296/7327). Each SD decrease in radius cortical bone measures increased fracture risk by 38%-76% for women and men. After additional adjustment for FN-aBMD, risks remained increased by 28%-61%. Radius trabecular measures were also associated with 2-year fracture risk independently of FN-aBMD in women (HRs range: 1.21 per SD for trabecular separation to 1.55 for total vBMD). Decreased failure load (FL) was associated with increased fracture risk in both women and men (FN-aBMD ranges of adjusted HR = 1.47-2.42). Tibia measurement results were similar to radius results. Findings were also similar when models were adjusted for FRAX. In older adults, FL and HR-pQCT measures of cortical and trabecular bone microarchitecture and density with strong associations to short-term fractures improved fracture prediction beyond aBMD and FRAX. Thus, HR-pQCT may be a useful adjunct to traditional assessment of short-term fracture risk in older adults, including those with T-scores above the osteoporosis range.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"1574-1583"},"PeriodicalIF":5.1,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11523184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142138794","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":"Deapi-platycodin D3 attenuates osteoarthritis development via suppression of PTP1B.","authors":"Liangliang Liu, Zihao Yao, Haiyan Zhang, Chunyu Wu, Xiongtian Guo, Yongzhi Lin, Hongbo Zhang, Chun Zeng, Xiaochun Bai, Daozhang Cai, Pinglin Lai","doi":"10.1093/jbmr/zjae149","DOIUrl":"10.1093/jbmr/zjae149","url":null,"abstract":"<p><p>Dysregulated chondrocyte metabolism is an essential risk factor for osteoarthritis (OA) progression. Maintaining cartilage homeostasis represents a promising therapeutic strategy for the treatment of OA. However, no effective disease-modifying therapy is currently available to OA patients. To discover potential novel drugs for OA, we screened a small-molecule natural product drug library and identified deapi-platycodin D3 (D-PDD3), which was subsequently tested for its effect on extracellular matrix (ECM) properties and on OA progression. We found that D-PDD3 promoted the generation of ECM components in cultured chondrocytes and cartilage explants and that intra-articular injection of D-PDD3 delayed disease progression in a trauma-induced mouse model of OA. To uncover the underlying molecular mechanisms supporting these observed functions of D-PDD3, we explored the targets of D-PDD3 via screening approach integrating surface plasmon resonance with liquid chromatography-tandem mass spectrometry. The results suggested that D-PDD3 targeted tyrosine-protein phosphatase non-receptor type 1 (PTP1B), deletion of which restored chondrocyte homeostasis and markedly attenuated destabilization of the medial meniscus induced OA. Further cellular and molecular analyses showed that D-PDD3 maintained cartilage homeostasis by directly binding to PTP1B and consequently suppressing the PKM2/AMPK pathway. These findings demonstrated that D-PDD3 was a potential therapeutic drug for the treatment of OA and that PTP1B served as a protein target for the development of drugs to treat OA. This study provided significant insights into the development of therapeutics for OA treatment, which, in turn, helped to improve the quality of life of OA patients and to reduce the health and economic burden.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"1673-1687"},"PeriodicalIF":5.1,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142277662","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}