Bone Reports最新文献

{"title":"Development of fatty acid analogues with potent anabolic effects on bone in male mice","authors":"Jian-ming Lin ,&nbsp;Ivo Dimitrov ,&nbsp;Karen E. Callon ,&nbsp;Maureen Watson ,&nbsp;Ian R. Reid ,&nbsp;William A. Denny ,&nbsp;Jillian Cornish","doi":"10.1016/j.bonr.2025.101862","DOIUrl":"10.1016/j.bonr.2025.101862","url":null,"abstract":"<div><div>Natural fatty acids are inhibitory to osteoclastogenesis, but only mildly so, as reported earlier by our and other groups. To improve the potency, we have synthesized two categories of analogues based on the backbone of saturated palmitic acid by inserting an ether or a triazole group in the carbon chain. The most effective compound proved to be with a triazole moiety farthest away from the acid unit. Following this strategy, we now have developed even more potent molecules, methylated triazole and tetrazole analogues. Tetrazole analogue displays about 10-fold higher inhibitory activity over the natural counterpart as tested in the osteoclastogenesis assay using mouse bone marrow cell cultures. Importantly, this inhibition is not due to cytotoxicity as both the methylated triazole and tetrazole molecules slightly increase the viability of bone marrow cells. It was found that the inhibition of osteoclastogenesis by the tetrazole analogue in mouse bone marrow cultures is associated with the decreased expression of the key osteoclastogenic or osteoclastic marker genes: <em>Dcstamp</em>, <em>Nfatc1</em>, <em>Tnfa</em>, <em>Trap</em> and <em>Ctsk</em>. The best analogue-tetrazole was then tested <em>in vivo</em> in a mouse calvarial local injection model after being solubilized by (2-hydroxypropyl)-β-cyclodextrin (β-CD). The results show that the tetrazole at the daily dose of 40 μg/injection (along with 264 μg β-CD) significantly reduce TRAP surface, and significantly increased mineralizing surface/bone surface, mineral apposition rate and bone formation rate. This study provides a novel effective agent for inhibiting osteoclastogenesis and positively regulating bone homeostasis.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"26 ","pages":"Article 101862"},"PeriodicalIF":2.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144779432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Osteoblasts sense extracellular levels of phosphate to control the local expression of phosphatases for matrix mineralisation","authors":"Soher Nagi Jayash,&nbsp;Thomas Duff,&nbsp;Qaisar Tanveer,&nbsp;Worachet Promruk,&nbsp;Colin Farquharson","doi":"10.1016/j.bonr.2025.101863","DOIUrl":"10.1016/j.bonr.2025.101863","url":null,"abstract":"<div><div>The provision of inorganic phosphate (P_i) for biomineralisation is under systemic and local control. Locally, osteoblast production of phosphatases such as tissue-nonspecific alkaline phosphatase (TNAP) and PHOSPHO1 is required for normal skeletal mineralisation and osteoblasts may sense extracellular P_i concentrations to control local phosphatase activity and thereby “fine-tune” P_i production and delivery for biomineralisation. This has been poorly explored and this study examined the ability of osteoblasts to sense and respond to extracellular P_i to control the local expression of TNAP and PHOSPHO1.</div><div>Extracellular P_i downregulated the expression of PHOSPHO1 and TNAP by human primary osteoblasts at both mRNA and protein levels. Increasing P_i concentrations also reduced the mRNA expression of the type III Na- P_i co-transporters, PiT-1 and PiT-2 and selectively enhanced ERK1/2 phosphorylation. Inhibition of PiT-1 and PiT-2 by Foscarnet or MEK1/2 by UO126 abolished the downregulation of <em>PHOSPHO1</em> and <em>ALPL</em> expression by extracellular Pi. Moreover, extracellular P_i phosphorylated fibroblast growth factor receptor (FGFR) substrate 2α (FRS2α) and this activation was abolished by Foscarnet. Also, blocking FGFR signalling inhibited the phosphorylation of ERK1/2 and prevented the decrease in <em>ALPL</em> and <em>PHOSPHO1</em> expression by extracellular P_i. Similar results were observed in cultured murine calvaria. Osteoblast matrix mineralisation by extracellular P_i was dependent upon type III Na- P_i co-transporters and FGFR signalling.</div><div>In conclusion, these results suggest an interplay between FGFR and P_i transporters is required for osteoblasts to sense and respond to extracellular P_i. This understanding advances our knowledge of the molecular control of physiological bone mineralisation by osteoblasts.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"26 ","pages":"Article 101863"},"PeriodicalIF":2.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144750368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Experimental analysis of bone marrow adipose tissue and bone marrow adipocytes: An update from the bone marrow adiposity society (BMAS)","authors":"Michaela Tencerova ,&nbsp;Biagio Palmisano ,&nbsp;Stéphanie Lucas ,&nbsp;Camille Attané ,&nbsp;Kaisa K. Ivaska ,&nbsp;Léa Loisay ,&nbsp;Yoshiko M. Ikushima ,&nbsp;Drenka Trivanovic ,&nbsp;Alessandro Corsi ,&nbsp;Adriana Roque ,&nbsp;Hongshuai Li ,&nbsp;Friederike Behler-Janbeck ,&nbsp;Jeroen Geurts ,&nbsp;Mara Riminucci ,&nbsp;Izabela Podgorski ,&nbsp;William P. Cawthorn ,&nbsp;Bram C.J. van der Eerden ,&nbsp;André J. van Wijnen","doi":"10.1016/j.bonr.2025.101861","DOIUrl":"10.1016/j.bonr.2025.101861","url":null,"abstract":"<div><div>Bone marrow adipose tissue (BMAT) is physiologically linked to bone and energy metabolism, endocrine regulation, hematopoiesis and cancer-related processes. A key challenge in the field is that methods for isolating BMAT or bone marrow adipocytes (BMAds) are variable because there are no widely adopted standardized protocols. To generate awareness of this challenge and to establish uniformity in experimental approaches requiring isolation, storage and characterization of BMAT and BMAds, the Biobanking Working Group of the international Bone Marrow Adiposity Society (BMAS) has previously recommended experimental standards. This paper provides an update on this effort and presents current state-of-the-art methods and technical considerations for isolation and characterization of BMAT and BMAds, including currently available high-throughput omics approaches. This review provides a reference point based on the consensus view of BMAS investigators to support studies on biomedical, biological, biochemical and biophysical questions associated with bone marrow adiposity.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"26 ","pages":"Article 101861"},"PeriodicalIF":2.6,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144828523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of denosumab combination with proximal femoral nail antirotation surgery in elderly patients with intertrochanteric femoral fractures: A comparative study","authors":"Xiaoqing Lu,&nbsp;Jun Zhu,&nbsp;Bai Zheng,&nbsp;Junsheng Wang","doi":"10.1016/j.bonr.2025.101860","DOIUrl":"10.1016/j.bonr.2025.101860","url":null,"abstract":"<div><h3>Objective</h3><div>To evaluate the effect of denosumab combined with proximal femoral nail antirotation (PFNA) surgery in elderly patients with osteoporotic intertrochanteric femoral fractures (ITF Fx).</div></div><div><h3>Design and Setting</h3><div>This retrospective, comparative study included patients aged ≥65 years with osteoporotic ITF Fx who underwent PFNA fixation at Huai'an Second People's Hospital between July 2021 and July 2023.</div></div><div><h3>Participants</h3><div>Pain relief (visual analogue scale, VAS), hip function, bone mineral density (BMD), time to fracture healing, refracture rate, and adverse events were compared.</div></div><div><h3>Interventions</h3><div>This is a retrospective study, without the addition of any intervention measures.</div></div><div><h3>Results</h3><div>A total of 76 patients were included, with 38 patients in the denosumab + PFNA group and 38 in the PFNA group. The denosumab + PFNA group showed significantly greater improvements in pain relief (1.68 ± 0.93 vs 2.29 ± 0.97, <em>p</em> = 0.014) and BMD T-score (−1.49 ± 0.61 vs −1.98 ± 0.52, <em>p</em> = 0.006) at 12 months compared to the PFNA group. Fracture healing time was significantly shorter in the denosumab + PFNA group (12.37 ± 1.38 vs 13.63 ± 1.34 weeks, <em>p</em> &lt; 0.001), and the refracture rate was significantly lower (2.63 % vs 21.05 %, <em>p</em> &lt; 0.05) than that in the PFNA group. The post-treatment hip function was comparable between the denosumab + PFNA and PFNA groups. Only one case of hypocalcemia was reported in the denosumab + PFNA group (2.63 %).</div></div><div><h3>Conclusion</h3><div>Denosumab combined with PFNA surgery might have an advantage in pain relief, BMD T-score, and fracture healing, while reducing refracture risk in elderly patients with osteoporotic ITF Fx compared with PFNA surgery alone.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"26 ","pages":"Article 101860"},"PeriodicalIF":2.1,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144713413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The supercritical CO2 process does not affect the mechanical properties and the microarchitecture of trabecular bone at the microscopic scale: A microindentation and microcomputed tomography study","authors":"Théo Krieger ,&nbsp;Virginie Taillebot ,&nbsp;Aurélien Maurel-Pantel ,&nbsp;Claire Camy ,&nbsp;Grégoire Edorh ,&nbsp;Matthieu Ollivier ,&nbsp;Martine Pithioux","doi":"10.1016/j.bonr.2025.101859","DOIUrl":"10.1016/j.bonr.2025.101859","url":null,"abstract":"<div><div>Bone allografts are frequently used in many surgical procedures because of their osteoconductive and osteoinductive properties. After being extracted from the donor, the graft is treated with a process that cleans and sterilizes it before being implanted in the patient. While they guarantee the safety of the patient receiving the graft, preservation processes often affect bone properties.</div><div>This study aims to measure the effect of a supercritical CO₂ process on the microarchitecture and the mechanical properties of trabecular bone at a microscopic scale using microindentation. 7 femoral heads were harvested from patients who had undergone a total hip arthroplasty. 42 cubic samples of 10 mm side from these femoral heads were randomly distributed in 3 groups: frozen at −20 °C, gamma irradiated and frozen at −20 °C, and treated with a supercritical CO₂ process including gamma irradiation. All samples were imaged by microtomography and characterized by microindentation to correlate the bone microarchitecture with the mechanical properties at a microscopic scale.</div><div>Our results show that the supercritical CO₂ process exerts no significant effect on the microarchitecture parameters, indentation elastic modulus, and indentation hardness.</div><div>The correlations between the microarchitecture and the mechanical properties revealed that gamma irradiation appears to induce a slight alteration in mechanical properties. However, the process combining a supercritical CO₂ treatment and gamma irradiation does not induce any more alterations to the material than gamma irradiation itself. Thus, the supercritical CO₂ process has no more impact than gamma irradiation on the mechanical properties of trabecular bone at the microscopic scale.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"26 ","pages":"Article 101859"},"PeriodicalIF":2.1,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144703986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abaloparatide effects on BMD in acetabular regions corresponding to DeLee and Charnley zones in women with postmenopausal osteoporosis","authors":"Neil P. Sheth ,&nbsp;Kelly Krohn ,&nbsp;Jared Torkelson ,&nbsp;Renaud Winzenrieth ,&nbsp;Ludovic Humbert ,&nbsp;Leny Pearman ,&nbsp;Yamei Wang ,&nbsp;John I. Boxberger ,&nbsp;Mathias P. Bostrom","doi":"10.1016/j.bonr.2025.101858","DOIUrl":"10.1016/j.bonr.2025.101858","url":null,"abstract":"<div><h3>Background</h3><div>Acetabular bone loss in patients with osteoporosis is associated with increased risk of acetabular fragility fractures, significant morbidity, and can increase risk of complications in patients undergoing total hip arthroplasty. The anabolic osteoporosis treatment abaloparatide increases total hip areal bone mineral density (BMD), but its effect on acetabular BMD is unknown.</div></div><div><h3>Methods</h3><div>Anatomical landmarks were identified in DXA scans from a random subgroup of postmenopausal women with osteoporosis (PMO) treated with abaloparatide 80 μg/d or placebo (n = 250/group) from the phase 3 ACTIVE trial to virtually place a hemispherical shell model of an acetabular cup and define regions of interest corresponding to DeLee and Charnley zones 1 (R1), 2 (R2), and 3 (R3). Changes in BMD from baseline at 6 and 18 months were calculated. Statistical significance was tested using a mixed model with repeated measures. Local mean changes in BMD were depicted by alignment of DXA scans via intensity-based registration onto a reference scan.</div></div><div><h3>Results</h3><div>Abaloparatide significantly increased acetabular areal BMD in all three DeLee and Charnley zones at 6 and 18 months versus placebo. Mean BMD increases with abaloparatide were 8.38 % (R1), 7.25 % (R2), and 9.73 % (R3) at 18 months. BMD increases were homogenously distributed throughout the regions. With placebo, localized losses in BMD were noted after 18 months.</div></div><div><h3>Conclusions</h3><div>Abaloparatide treatment rapidly and progressively increases BMD in acetabular zones in PMO.</div></div><div><h3>Clinical trial number</h3><div><span><span>NCT01343004</span><svg><path></path></svg></span>.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"26 ","pages":"Article 101858"},"PeriodicalIF":2.6,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144723965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multigenerational genetic inheritance and clinical characteristics of the rare disease hypophosphatasia in 6 families: A case series","authors":"Peter Kannu ,&nbsp;Aliya A. Khan ,&nbsp;Mira Francis ,&nbsp;Jonathan D. Adachi","doi":"10.1016/j.bonr.2025.101857","DOIUrl":"10.1016/j.bonr.2025.101857","url":null,"abstract":"<div><div>Family mapping is a useful tool for tracking the inheritance of rare inherited diseases, including hypophosphatasia (HPP), through generations. We show the inheritance of HPP in 6 affected families, describing genetic variants, biochemical hallmarks, and clinical manifestations among family members. Mapping families with HPP is warranted in clinical practice to better understand monitoring needs for potentially affected individuals over time, since manifestations of HPP can arise throughout a patient's lifespan.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"26 ","pages":"Article 101857"},"PeriodicalIF":2.1,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144703987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"VEGF-A, -C, -D, VEGFR1, -2, -3, PDGF-BB and FGF-2 join forces to induce vascular and lymphatic angiogenesis during bone healing of hip implants","authors":"Jean Cassuto ,&nbsp;Agnetha Folestad ,&nbsp;Jan Göthlin ,&nbsp;Henrik Malchau ,&nbsp;Johan Kärrholm","doi":"10.1016/j.bonr.2025.101856","DOIUrl":"10.1016/j.bonr.2025.101856","url":null,"abstract":"<div><h3>Introduction</h3><div>Angiogenic growth factors are a critical part of bone repair and regeneration in the aftermath of bone trauma. In the current study we monitored the spatiotemporal responses of angiogenic factors and receptors during the process of osseointegration of hip implants.</div></div><div><h3>Materials and methods</h3><div>Twenty-four patients having undergone primary total hip arthroplasty (THA) due to one-sided osteoarthritis (OA) were monitored during a period of 18 years (Y) by repeated measurements of plasma biomarkers as well as clinical and radiographic variables, the latter two showing all implants of the study to be well anchored throughout the follow-up. Eighty-one healthy donors divided into three gender- and age-matched subgroups and twenty OA patients awaiting THA, served as controls. Plasma was analyzed for vascular endothelial growth factor (VEGF)-A, VEGF-C, VEGF-D, vascular endothelial growth factor receptor 1 (VEGFR1) or sFlt-1, VEGFR2 (KDR/sFlk-1), VEGFR3 (sFlt-4), platelet derived growth factor–BB (PDGF-BB), fibroblast growth factor-2 (FGF-2) and placental growth factor (PIGF). Analysis of biomarkers was done by means of a high-sensitivity and wide dynamic range electrochemiluminescence technique allowing for detection of low levels and minor changes in biomarker levels. Spatiotemporal changes of biomarkers in THA patients during the follow-up were presented in the context of the four phases of endochondral bone repair.</div></div><div><h3>Results</h3><div>VEGF-A, VEGFR1, PDGF-BB and FGF-2 were significantly higher, whereas VEGF-C was significantly lower in presurgery OA patients versus healthy subjects but were all normalized shortly after implant surgery. VEGF-A, VEGF-C, VEGF-D, VEGFR2, VEGFR3, FGF-2 and PDGF-BB increased sharply 1–2 Y post-implant and reached a peak significantly above healthy control subjects at 5–7 Y after implant insertion before returning to control level 13-15Y post-surgery, except for VEGF-D that returned to control level at 7Y post-implant. VEGFR1 decreased to the level of healthy subjects at 6 W post-THA and remained there throughout the study. PIGF did not differ from healthy subjects at any point during the follow-up.</div></div><div><h3>Conclusion</h3><div>Increased levels of VEGF-A, VEGFR1, PDGF-BB and FGF-2 and reduced VEGF-C in presurgery OA relative healthy subjects support a cartilage protective or disease-inducing role in osteoarthritis. The concerted increase by all proangiogenic factors of the study, except VEGFR1 and PIGF, at 5 Y post-implant lend strong support to this being the phase of bone repair when blood and lymph vessels invade the avascular calcified hypertrophic cartilage and trigger its remodeling into bone in hip arthroplasty patients.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"26 ","pages":"Article 101856"},"PeriodicalIF":2.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144570851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fluorescent collagen hybridizing peptide for quantifying collagen denaturation in cortical bone","authors":"William Woolley ,&nbsp;Naomi Chin ,&nbsp;S. Michael Yu ,&nbsp;Claire Acevedo","doi":"10.1016/j.bonr.2025.101855","DOIUrl":"10.1016/j.bonr.2025.101855","url":null,"abstract":"<div><div>Bone fracture risk is clinically assessed with bone mineral density (BMD); however, individuals with normal BMD also experience fractures, highlighting the need for complementary fracture risk assessment tools. While BMD remains the clinical gold standard, it fails to capture bone quality factors that contribute to fragility. Among these, collagen quality is essential for bone toughness, as it allows collagen to dissipate energy via stretching and uncoiling. When collagen is denatured, it loses its ability to deform, increasing fracture risk. This process is particularly relevant in aging, osteoporosis, and metabolic conditions such as diabetes, yet no clinical methods exist to quantify or localize denatured collagen in mineralized bone. This study introduces Collagen Hybridizing Peptide (CHP) as a tool to quantify denatured collagen in cortical bone. Here, we show that CHP fluorescence correlates strongly with collagen denaturation measured by established trypsin-hydroxyproline assay (r² = 0.99) when applied to mineralized tissue subjected to heat treatment or mechanical loading. Confocal microscopy revealed a 55 % increase in collagen denaturation when tissue strain exceeded the yield point (<em>p</em> <em>&lt;</em> 0.05). Our findings demonstrate that fluorescent CHP localizes high-strain regions to collagen denaturation on bone fracture surfaces, indicating that collagen damage occurs during post-yield failure. This non-destructive technique offers a powerful tool for assessing collagen quality, with potential applications in osteoporosis, diabetic bone fragility, and aging research. By advancing our ability to evaluate bone quality in cortical bone, R-CHP provides new method to study how denatures collagen affects bone resistance to fracture.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"26 ","pages":"Article 101855"},"PeriodicalIF":2.1,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144501282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"p75NTR regulates postnatal skeletal development via NGF-responsive JNK signaling","authors":"Chiho Kadota-Watanabe ,&nbsp;Jinsook Suh ,&nbsp;Zhenqing Liu ,&nbsp;Eric Yin ,&nbsp;Kate Lindsey ,&nbsp;Isabelle Lao-Ngo ,&nbsp;Byron Zhao ,&nbsp;Jonathan H. Wu ,&nbsp;In Won Chang ,&nbsp;Reuben H. Kim ,&nbsp;Ophir D. Klein ,&nbsp;Christine Hong","doi":"10.1016/j.bonr.2025.101854","DOIUrl":"10.1016/j.bonr.2025.101854","url":null,"abstract":"<div><div>p75^NTR has emerged as a key regulator of skeletal development and bone homeostasis. To define its role, we characterized skeletal phenotypes in global and mesenchyme-specific <em>p75</em>^<em>NTR</em> knockout mouse models. Global deletion of <em>p75</em>^<em>NTR</em> resulted in postnatal growth retardation, decreased trabecular and cortical bone mass, and impaired growth plate architecture—hallmarks of an osteoporotic phenotype that persisted into adulthood. Conditional deletion of <em>p75</em>^<em>NTR</em> in mesenchymal progenitor cells using Prx1-Cre recapitulated these skeletal deficits, confirming a cell-autonomous role in bone development. In vitro, bone marrow stromal cells (BMSCs) derived from <em>p75</em>^<em>NTR</em>-deficient mouse exhibited diminished osteogenic differentiation capacity, reduced mineralization, and downregulation of key osteogenic genes. Transcriptomic profiling revealed significant suppression of the NGF-MAPK/AP-1 signaling axis in <em>p75</em>^<em>NTR</em>-deficient BMSCs. Functional studies demonstrated that loss of <em>p75</em>^<em>NTR</em> reduced JNK pathway activation and downstream epigenetic regulators, including <em>Kdm4b</em> and its target gene <em>Dlx5</em>. Overexpression of <em>Kdm4b</em> rescued mineralization defects and restored osteogenic gene expression in <em>p75</em>^<em>NTR</em>-deficient BMSCs, establishing a mechanistic link between p75^NTR signaling and osteoblast differentiation. These findings define the NGF–p75^NTR–JNK–KDM4B<em>–Dlx5</em> axis as a central regulatory pathway in postnatal bone growth and osteogenesis. Given the critical role of p75^NTR in skeletal development and bone homeostasis, targeted modulation of this signaling cascade may represent a promising therapeutic approach for treating osteoporosis and other bone disorders.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"26 ","pages":"Article 101854"},"PeriodicalIF":2.1,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144322046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}