Bone最新文献

{"title":"The role of bone in energy metabolism: A focus on osteocalcin","authors":"Cassandra Smith ,&nbsp;Xuzhu Lin ,&nbsp;Lewan Parker ,&nbsp;Bu B. Yeap ,&nbsp;Alan Hayes ,&nbsp;Itamar Levinger","doi":"10.1016/j.bone.2024.117238","DOIUrl":"10.1016/j.bone.2024.117238","url":null,"abstract":"<div><p>Understanding the mechanisms involved in whole body glucose regulation is key for the discovery of new treatments for type 2 diabetes (T2D). Historically, glucose regulation was largely focused on responses to insulin and glucagon. Impacts of incretin-based therapies, and importance of muscle mass, are also highly relevant. Recently, bone was recognized as an endocrine organ, with several bone proteins, known as osteokines, implicated in glucose metabolism through their effects on the liver, skeletal muscle, and adipose tissue. Research efforts mostly focused on osteocalcin (OC) as a leading example. This review will provide an overview on this role of bone by discussing bone turnover markers (BTMs), the receptor activator of nuclear factor kB ligand (RANKL), osteoprotegerin (OPG), sclerostin (SCL) and lipocalin 2 (LCN2), with a focus on OC. Since 2007, some, but not all, research using mostly OC genetically modified animal models suggested undercarboxylated (uc) OC acts as a hormone involved in energy metabolism. Most data generated from in vivo, ex vivo and in vitro models, indicate that exogenous ucOC administration improves whole-body and skeletal muscle glucose metabolism. Although data in humans are generally supportive, findings are often discordant likely due to methodological differences and observational nature of that research. Overall, evidence supports the concept that bone-derived factors are involved in energy metabolism, some having beneficial effects (ucOC, OPG) others negative (RANKL, SCL), with the role of some (LCN2, other BTMs) remaining unclear. Whether the effect of osteokines on glucose regulation is clinically significant and of therapeutic value for people with insulin resistance and T2D remains to be confirmed.</p></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"188 ","pages":"Article 117238"},"PeriodicalIF":3.5,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S8756328224002278/pdfft?md5=2d7b60dc412ed76cc740d21422101b7e&pid=1-s2.0-S8756328224002278-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141997076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"3D osteocyte lacunar morphometry of human bone biopsies with high resolution microCT: From monoclonal gammopathy to newly diagnosed multiple myeloma","authors":"Inés Moreno-Jiménez ,&nbsp;Sharen Heinig ,&nbsp;Unai Heras ,&nbsp;Daniela Simone Maichl ,&nbsp;Susanne Strifler ,&nbsp;Ellen Leich ,&nbsp;Stéphane Blouin ,&nbsp;Peter Fratzl ,&nbsp;Nadja Fratzl-Zelman ,&nbsp;Franziska Jundt ,&nbsp;Amaia Cipitria","doi":"10.1016/j.bone.2024.117236","DOIUrl":"10.1016/j.bone.2024.117236","url":null,"abstract":"<div><p>Osteocytes are mechanosensitive, bone-embedded cells which are connected via dendrites in a lacuno-canalicular network and regulate bone resorption and formation balance. Alterations in osteocyte lacunar volume, shape and density have been identified in conditions of aging, osteoporosis and osteolytic bone metastasis, indicating patterns of impaired bone remodeling, osteolysis and disease progression. Osteolytic bone disease is a hallmark of the hematologic malignancy multiple myeloma (MM), in which monoclonal plasma cells in the bone marrow disrupt the bone homeostasis and induce excessive resorption at local and distant sites. Qualitative and quantitative changes in the 3D osteocyte lacunar morphometry have not yet been evaluated in MM, nor in the precursor conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). In this study, we characterized the osteocyte lacunar morphology in trabecular bone of the iliac crest at the ultrastructural level using high resolution microCT in human bone biopsy samples of three MGUS, two SMM and six newly diagnosed MM. In MGUS, SMM and MM we found a trend for lower lacunar density and a shift towards larger lacunae with disease progression (higher 50 % cutoff of the lacunar volume cumulative distribution) in the small osteocyte lacunae 20–900 μm³ range compared to control samples. In the larger lacunae 900–3000 μm³ range, we detected significantly higher lacunar density and microporosity in the MM group compared to the MGUS/SMM group. Regarding the shape distribution, the MGUS/SMM group showed a trend for flatter, more elongated and anisotropic osteocyte lacunae compared to the control group. Altogether, our findings suggest that osteocytes in human MM bone disease undergo changes in their lacunae density, volume and shape, which could be an indicator for osteolysis and disease progression. Future studies are needed to understand whether alterations of the lacunae architecture affect the mechanoresponsiveness of osteocytes, and ultimately bone adaptation and fracture resistance in MM and its precursors conditions.</p></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"189 ","pages":"Article 117236"},"PeriodicalIF":3.5,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S8756328224002254/pdfft?md5=91e82e606b5aecf599b723475ea2e9c5&pid=1-s2.0-S8756328224002254-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141997075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitigating aging and doxorubicin induced bone loss in mature mice via mechanobiology based treatments","authors":"Murtaza Wasi ,&nbsp;Tiankuo Chu ,&nbsp;Rosa M. Guerra ,&nbsp;Rory Kooker ,&nbsp;Kenneth Maldonado ,&nbsp;Xuehua Li ,&nbsp;Chun-Yu Lin ,&nbsp;Xin Song ,&nbsp;Jinhu Xiong ,&nbsp;Lidan You ,&nbsp;Liyun Wang","doi":"10.1016/j.bone.2024.117235","DOIUrl":"10.1016/j.bone.2024.117235","url":null,"abstract":"<div><p>Aging leads to a reduced anabolic response to mechanical stimuli and a loss of bone mass and structural integrity. Chemotherapy agents such as doxorubicin exacerbate the degeneration of aging skeleton and further subject older cancer patients to a higher fracture risk. To alleviate this clinical problem, we proposed and tested a novel mechanobiology-based therapy. Building upon prior findings that i) Yoda1, the Piezo1 agonist, promoted bone growth in young adult mice and suppressed bone resorption markers in aged mice, and ii) moderate tibial loading protected bone from breast cancer-induced osteolysis, we hypothesized that combined Yoda1 and moderate loading would improve the structural integrity of adult and aged skeletons in vivo and protect bones from deterioration after chemotherapy. We first examined the effects of 4-week Yoda1 (dose 5 mg/kg, 5 times/week) and moderate tibial loading (4.5 N peak load, 4 Hz, 300 cycles for 5 days/week), individually and combined, on mature mice (∼50 weeks of age). Combined Yoda1 and loading was found to mitigate age-associated cortical and trabecular bone loss better than individual interventions. As expected, the non-treated controls experienced an average drop of cortical polar moment of inertia (Ct.pMOI) by −4.3 % over four weeks and the bone deterioration occurred in the majority (64 %) of the samples. Relative to no treatment, loading alone, Yoda1 alone, and combined Yoda1 and loading increased Ct.pMOI by +7.3 %, +9.5 %, +12.0 % and increased the % of samples with positive Ct.pMOI changes by +32 %, +26 %, and +43 %, respectively, suggesting an additive protection of aging-related bone loss for the combined therapy. We further tested if the treatment efficacy was preserved in mature mice following two weeks (six injections) of doxorubicin at the dose of 2.5 or 5 mg/kg. As expected, doxorubicin increased osteocyte apoptosis, altered bone remodeling, and impaired bone structure. However, the effects induced by DOX were too severe to be rescued by Yoda1 and loading, alone or combined, although loading and Yoda1 individually, or combined, increased the number of mice showing positive responsiveness by 0 %, +15 %, and +29 % relative to no intervention after doxorubicin exposure. Overall, this study supported the potentials and challenges of the Yoda1-based strategy in mitigating the detrimental skeletal effects caused by aging and doxorubicin.</p></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"188 ","pages":"Article 117235"},"PeriodicalIF":3.5,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141989787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A GCaMP reporter mouse with chondrocyte specific expression of a green fluorescent calcium indicator","authors":"Sotirios A. Tsadaris ,&nbsp;David E. Komatsu ,&nbsp;Vladimir Grubisic ,&nbsp;Raddy L. Ramos ,&nbsp;Michael Hadjiargyrou","doi":"10.1016/j.bone.2024.117234","DOIUrl":"10.1016/j.bone.2024.117234","url":null,"abstract":"<div><p>One of the major processes occurring during the healing of a fractured long bone is chondrogenesis, leading to the formation of the soft callus, which subsequently undergoes endochondral ossification and ultimately bridges the fracture site. Thus, understanding the molecular mechanisms of chondrogenesis can enhance our knowledge of the fracture repair process. One such molecular process is calciun (Ca⁺⁺) signaling, which is known to play a critical role in the development and regeneration of multiple tissues, including bone, in response to external stimuli. Despite the existence of various mouse models for studying Ca⁺⁺ signaling, none of them were designed to specifically examine the skeletal system or the various musculoskeletal cell types. As such, we generated a genetically engineered mouse model that is specific to cartilage (crossed with Col2a1 Cre mice) to study chondrocytes. Herein, we report on the characterization of this transgenic mouse line using conditional expression of GCaMP6f, a Ca⁺⁺-indicator protein. Specifically, this mouse line exhibits increased GCaMP6f fluorescence following Ca⁺⁺ binding in chondrocytes. Using this model, we show real-time Ca⁺⁺ signaling in embryos, newborn and adult mice, as well as in fracture calluses. Further, robust expression of GCaMP6f in chondrocytes can be easily detected in embryos, neonates, adults, and fracture callus tissue sections. Finally, we also report on Ca⁺⁺ signaling pathway gene expression, as well as real-time Ca⁺⁺ transient measurements in fracture callus chondrocytes. Taken together, these mice provide a new experimental tool to study chondrocyte-specific Ca⁺⁺ signaling during skeletal development and regeneration, as well as various <em>in vitro</em> perturbations.</p></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"188 ","pages":"Article 117234"},"PeriodicalIF":3.5,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141985038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cross-sectional size, shape, and estimated strength of the tibia, fibula and second metatarsal in female collegiate-level cross-country runners and soccer players","authors":"Austin M. Sventeckis ,&nbsp;Rachel K. Surowiec ,&nbsp;Robyn K. Fuchs ,&nbsp;Stuart J. Warden","doi":"10.1016/j.bone.2024.117233","DOIUrl":"10.1016/j.bone.2024.117233","url":null,"abstract":"<div><p>Bone stress injuries (BSIs) frequently occur in the leg and foot long bones of female distance runners. A potential means of preventing BSIs is to participate in multidirectional sports when younger to build a more robust skeleton. The current cross-sectional study compared differences in tibia, fibula, and second metatarsal diaphysis size, shape, and strength between female collegiate-level athletes specialized in cross-country running (RUN, <em>n</em> = 16) and soccer (SOC, n = 16). Assessments were performed using high-resolution peripheral quantitative computed tomography and outcomes corrected for measures at the radius diaphysis to control for selection bias and systemic differences between groups. The tibia in SOC had a 7.5 % larger total area than RUN, with a 29.4 % greater minimum second moment of area (I_MIN) and 8.2 % greater estimated failure load (all <em>p</em> ≤ 0.02). Tibial values in SOC exceeded reference data indicating positive adaptation. In contrast, values in RUN were similar to reference data suggesting running induced limited tibial adaptation. RUN did have a larger ratio between their maximum second moment of area (I_MAX) and I_MIN than both SOC and reference values. This suggests the unidirectional loading associated with running altered tibial shape with material distributed more in the anteroposterior (I_MAX) direction as opposed to the mediolateral (I_MIN) direction. Comparatively, SOC had a similar I_MAX/I_MIN ratio to reference data suggesting the larger tibia in SOC resulted from multiplane adaptation. In addition to enhanced size and strength of their tibia, SOC had enhanced structure and strength of their fibula and second metatarsal. At both sites, polar moment of inertia was approximately 25 % larger in SOC compared to RUN (all <em>p</em> = 0.03). These data support calls for young female athletes to delay specialization in running and participate in multidirectional sports, like soccer, to build a more robust skeleton that is potentially more protected against BSIs.</p></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"188 ","pages":"Article 117233"},"PeriodicalIF":3.5,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141914804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"miR-18a-5p promotes osteogenic differentiation of BMSC by inhibiting Notch2","authors":"Peipei He ,&nbsp;Zefeng Yang ,&nbsp;Hetong Li ,&nbsp;Enhui Zhou ,&nbsp;Zuoxu Hou ,&nbsp;Hongxun Sang","doi":"10.1016/j.bone.2024.117224","DOIUrl":"10.1016/j.bone.2024.117224","url":null,"abstract":"<div><p>Postmenopausal osteoporosis (PMOP) is a metabolic disorder characterized by the loss of bone density, which increases the risk of developing complications such as fractures. A pivotal factor contributing to the onset of PMOP is the diminished osteogenic differentiation capacity of bone marrow mesenchymal stem cells (BMSCs). MicroRNAs (miRNAs) play a substantial role in this process; however, their specific impact on regulating BMSCs osteogenesis remains unclear. Studies have evidenced a reduced expression of miR-18a-5p in PMOP, and concomitantly, our observations indicate an augmented expression of miR-18a-5p during the osteogenic differentiation of BMSCs. This investigation seeks to elucidate the regulatory influence of miR-18a-5p on BMSC osteogenic differentiation and the underlying mechanisms. In vitro experiments demonstrated that the overexpression of miR-18a-5p facilitated the osteogenic differentiation of BMSCs, while the downregulation of miR-18a-5p yielded converse outcomes. Mechanistically, We employed bioinformatics techniques to screen out the target gene Notch2 of miR-18a-5p. Subsequently, dual-luciferase reporter gene assays and rescue experiments substantiated that miR-18a-5p promotes BMSC osteogenic differentiation by suppressing Notch2. Finally, miR-18a-5p was overexpressed via adenovirus injection into the femoral bone marrow cavity, with results demonstrating its capability to enhance osteogenic differentiation and alleviate PMOP symptoms. Our findings disclose that miR-18a-5p fosters osteogenic differentiation of BMSC by inhibiting Notch2, thereby offering novel targets and strategies for PMOP treatment.</p></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"188 ","pages":"Article 117224"},"PeriodicalIF":3.5,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141908678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical frailty and short-term outcomes after low-energy pelvic fracture in the geriatric population: Nationwide inpatient sample 2016–2018 analysis","authors":"Yu-Cheng Lo ,&nbsp;Chih-Hui Chen ,&nbsp;Chiu Yu Shih ,&nbsp;Omar Toma","doi":"10.1016/j.bone.2024.117225","DOIUrl":"10.1016/j.bone.2024.117225","url":null,"abstract":"<div><h3>Background</h3><p>Pelvic fractures can be life-threatening for elderly individuals with diminished bone strength. Frailty is associated with fracture outcomes, but its impact on pelvic fracture recovery remains unexplored. The aim of this study was to investigate the association between frailty and short-term outcomes in older adults hospitalized for low-energy pelvic fractures.</p></div><div><h3>Methods</h3><p>Data from the Nationwide Inpatient Sample (NIS) covering the years 2005 to 2018 were reviewed. Inclusion criteria were age ≥ 60 years admitted for a low-energy pelvic fracture. Patients were categorized into frail and non-frail groups using the 11-factor modified Frailty Index (mFI-11). Association between frailty and in-hospital outcomes were determined by univariate and multivariable regression analyses.</p></div><div><h3>Results</h3><p>A total of 24,688 patients with pelvic fractures were included. The mean patient age was 80.6 ± 0.1 years, and 35 % were classified as frail. After adjustments, frailty was significantly associated with unfavorable discharge (adjusted odds ratio [aOR] = 1.07, 95 % confidence interval [CI]: 1.00–1.15, <em>p</em> = 0.038), prolonged hospitalization (aOR = 1.51, 95 % CI: 1.41–1.62, <em>p</em> &lt; 0.001), complications (aOR = 1.42, 95 % CI:1.34–1.50, <em>p</em> &lt; 0.001), and acute kidney injury (aOR = 1.68, 95 % CI: 1.56–1.82, p &lt; 0.001). Stratified analyses based on age and fracture type showed frailty was consistently associated with adverse outcomes.</p></div><div><h3>Conclusions</h3><p>Persons ≥60 years old with mFI-11 assessed frailty and a low-energy pelvic fracture are at higher risk of adverse in-hospital outcomes than non-frail patients. Additional research is needed to disclose the prognostic impact of clinical frailty on long-term functional outcomes and quality of life after discharge.</p></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"188 ","pages":"Article 117225"},"PeriodicalIF":3.5,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141908677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tartrate-resistant acid phosphatase (TRAP/ACP5) promotes bone length, regulates cortical and trabecular bone mass, and maintains growth plate architecture and width in a sex- and site-specific manner in mice","authors":"Bhavik Rathod ,&nbsp;Suchita Desai ,&nbsp;Hasmik Jasmine Samvelyan ,&nbsp;Laura Bock ,&nbsp;Jianyao Wu ,&nbsp;Claes Ohlsson ,&nbsp;Anders Palmquist ,&nbsp;Jessica J. Alm ,&nbsp;Phillip T. Newton ,&nbsp;Göran Andersson ,&nbsp;Sara H. Windahl","doi":"10.1016/j.bone.2024.117223","DOIUrl":"10.1016/j.bone.2024.117223","url":null,"abstract":"<div><p>Tartrate-resistant acid phosphatase (TRAP) serum levels reflect osteoclast number, bone remodeling activity, and fracture risk. Deletion or loss of function of TRAP results in short stature in mice and man. Yet, the impact and mechanisms of TRAP for the site- and sex-specific development of bone and cartilage is not well understood. Here, we use a global TRAP knockout (TRAPKO) and wildtype littermate control (WT) mice of both sexes to investigate TRAP as a possible sex- and site-specific regulator of bone and growth plate development. TRAPKO mice of both sexes weighed less and had shorter tibial length than their WT, features that were more accentuated in male than female TRAPKO mice. These changes were not associated with a general reduction in growth as not all organs displayed a proportionally lower mass, and serum IGF-1 was unchanged. Using μCT and site-specificity analysis of the cortical bone revealed wider proximal tibia, a higher trabecular thickness, and lower trabecular separation in male TRAPKO compared to WT mice, an effect not seen in female mice. Histomorphometric analysis revealed that the growth plate height as well as height of terminal hypertrophic chondrocytes were markedly increased, and the number of columns was decreased in TRAPKO mice of both sexes. These effects were more accentuated in female mice. Proliferation and differentiation of bone marrow derived macrophages into osteoclasts, as well as C-terminal cross links were normal in TRAPKO mice of both sexes. Collectively, our results show that TRAP regulates bone and cartilage development in a sex-and site-specific manner in mice.</p></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"188 ","pages":"Article 117223"},"PeriodicalIF":3.5,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S8756328224002126/pdfft?md5=3c65fd0152f17bcc619f2b71976358fd&pid=1-s2.0-S8756328224002126-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141903960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Estrogen and estrogen receptors mediate the mechanobiology of bone disease and repair","authors":"Vivian Shi,&nbsp;Elise F. Morgan","doi":"10.1016/j.bone.2024.117220","DOIUrl":"10.1016/j.bone.2024.117220","url":null,"abstract":"<div><p>It is well understood that the balance of bone formation and resorption is dependent on both mechanical and biochemical factors. In addition to cell-secreted cytokines and growth factors, sex hormones like estrogen are critical to maintaining bone health. Although the direct osteoprotective function of estrogen and estrogen receptors (ERs) has been reported extensively, evidence that estrogen signaling also has a role in mediating the effects of mechanical loading on maintenance of bone mass and healing of bone injuries has more recently emerged. Recent studies have underscored the role of estrogen and ERs in many pathways of bone mechanosensation and mechanotransduction. Estrogen and ERs have been shown to augment integrin-based mechanotransduction as well as canonical Wnt/b-catenin, RhoA/ROCK, and YAP/TAZ pathways. Estrogen and ERs also influence the mechanosensitivity of not only osteocytes but also osteoblasts, osteoclasts, and marrow stromal cells. The current review will highlight these roles of estrogen and ERs in cellular mechanisms underlying bone mechanobiology and discuss their implications for management of osteoporosis and bone fractures. A greater understanding of the mechanisms behind interactions between estrogen and mechanical loading may be crucial to addressing the shortcomings of current hormonal and pharmaceutical therapies. A combined therapy approach including high-impact exercise therapy may mitigate adverse side effects and allow an effective long-term solution for the prevention, treatment, and management of bone fragility in at-risk populations. Furthermore, future implications to novel local delivery mechanisms of hormonal therapy for osteoporosis treatment, as well as the effects on bone health of applications of sex hormone therapy outside of bone disease, will be discussed.</p></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"188 ","pages":"Article 117220"},"PeriodicalIF":3.5,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141899202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zoledronic acid relieves steroid-induced avascular necrosis of femoral head via inhibiting FOXD3 mediated ANXA2 transcriptional activation","authors":"Yu Lin ,&nbsp;Min Chen ,&nbsp;Wenbin Guo ,&nbsp;Shengliang Qiu ,&nbsp;Lihui Chen ,&nbsp;Wenge Liu","doi":"10.1016/j.bone.2024.117222","DOIUrl":"10.1016/j.bone.2024.117222","url":null,"abstract":"<div><h3>Background</h3><p>Zoledronic acid (ZOL) is a type of bisphosphonate with good therapeutic effects on orthopaedic diseases. However, the pharmacological functions of ZOL on steroid-induced avascular necrosis of femoral head (SANFH) and the underlying mechanism remain unclear, which deserve further research.</p></div><div><h3>Methods</h3><p>SANFH models both <em>in vivo</em> and <em>in vitro</em> were established by dexamethasone (Dex) stimulation. Osteoclastogenesis was examined by TRAP staining. Immunofluorescence was employed to examine autophagy marker (LC3) level. Cell apoptosis was analyzed by TUNEL staining. The interaction between Foxhead box D3 protein (FOXD3) and Annexin A2 (ANXA2) promoter was analyzed using ChIP and dual luciferase reporter gene assays.</p></div><div><h3>Results</h3><p>Dex aggravated osteoclastogenesis and induced osteoclast differentiation and autophagy <em>in vitro</em>, which was abrogated by ZOL treatment. PI3K inhibitor LY294002 abolished the inhibitory effect of ZOL on Dex-induced osteoclast differentiation and autophagy. FOXD3 overexpression neutralized the downregulation effects of ZOL on Dex-induced osteoclasts by transcriptionally activating ANXA2. ANXA2 knockdown reversed the effect of FOXD3 overexpression on ZOL-mediated biological effects in Dex-treated osteoclasts. In addition, ZOL improved SANFH symptoms in rats.</p></div><div><h3>Conclusion</h3><p>ZOL alleviated SANFH through regulating FOXD3 mediated ANXA2 transcriptional activity and then promoting PI3K/AKT/mTOR pathway, revealing that FOXD3 might be a target for ZOL in SANFH treatment.</p></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"188 ","pages":"Article 117222"},"PeriodicalIF":3.5,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141895089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}