Bone Reports最新文献

{"title":"A comparative analysis of bone mineral density in cerebral palsy and spinal muscular atrophy","authors":"Brianna G. Bowden ,&nbsp;Brett Klamer ,&nbsp;Robin Alexander ,&nbsp;Mariah Eisner ,&nbsp;Garey Noritz","doi":"10.1016/j.bonr.2025.101891","DOIUrl":"10.1016/j.bonr.2025.101891","url":null,"abstract":"<div><h3>Introduction</h3><div>Patients with cerebral palsy (CP) and spinal muscular atrophy (SMA) with immobility are at risk for low bone mineral density (BMD) and fragility fractures. This study investigates whether BMD differs between these two groups given their distinct pathological mechanisms.</div></div><div><h3>Methods</h3><div>Data were collected from non-ambulatory patients diagnosed with CP (GMFCS IV-V) and SMA (type I–II), aged five years and older, who were seen at a metabolic bone clinic between January 2012 and July 2023. Dual-energy X-ray absorptiometry (DXA) assessed BMD at the lumbar spine (LS) and lateral distal femur (LDF), region 3 (R3). Z-scores were calculated and compared between groups using the Wilcoxon rank sum test.</div></div><div><h3>Results</h3><div>This study included 274 children with CP and 16 with SMA. Unadjusted LS Z-scores were low and comparable in both groups (CP: −2.3, SMA: −2.6; p = 0.7). After adjusting for height, LS Z-scores were in the normal range (CP: −0.9, SMA: −1.6; p = 0.3). However, the SMA group had significantly lower BMD in R3 of the LDF compared to the CP group (CP: −2.9, SMA: −3.9; p = 0.047).</div></div><div><h3>Conclusion</h3><div>Both groups had normal height adjusted LS BMD and low R3 LDF BMD, with the SMA group significantly lower. We theorize that it may be due to the differences in muscle tonicity on the bone. We recommend including the distal femur bone density in routine bone health assessments and that BMD should be adjusted for height when possible.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"27 ","pages":"Article 101891"},"PeriodicalIF":2.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145690491","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":"Distinct osteoclastogenic potential of granulocyte-macrophage colony-stimulating factor-induced monocyte subsets","authors":"Shiho Kinoshita ,&nbsp;Yasuhiro Omata ,&nbsp;Kojiro Sato","doi":"10.1016/j.bonr.2025.101886","DOIUrl":"10.1016/j.bonr.2025.101886","url":null,"abstract":"<div><h3>Background</h3><div>Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and progressive bone destruction. Although osteoclasts mediate bone resorption in RA, recent evidence suggests that inflammatory osteoclasts differ from physiological osteoclasts in various aspects, including their progenitor origins. This study aimed to compare the osteoclastogenic potential of monocyte-derived dendritic cells (moDCs) and other granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced cells to identify potential progenitor populations involved in inflammatory bone damage.</div></div><div><h3>Methods</h3><div>Classical monocytes were isolated from human peripheral blood mononuclear cells and cultured under four conditions: (i) M-CSF, (ii) GM-CSF, (iii) GM-CSF + interleukin (IL)-4, and (iv) GM-CSF + tumor necrosis factor-alpha (TNF-α). Subsequently, to induce osteoclast differentiation, the cells were cultured with M-CSF and receptor activator of NF-κB ligand (RANKL) with or without the presence of GM-CSF, IL-4, and TNF-α, followed by evaluations via tartrate-resistant acid phosphatase (TRAP) staining and pit formation assays.</div></div><div><h3>Results</h3><div>Cells cultured with M-CSF, GM-CSF, and GM-CSF + TNF-α differentiated into TRAP-positive multinucleated osteoclasts with bone-resorbing activity. In contrast, moDCs (condition iii) exhibited minimal osteoclast differentiation without any bone-resorbing activity. Introduction of an intermediate M-CSF culture step induces adhesion of moDCs and partially induces osteoclastogenesis. However, their differentiation efficiency and bone resorption capacity remained inferior to those under other conditions. Notably, IL-4 and GM-CSF, but not TNF-α, suppressed osteoclast differentiation.</div></div><div><h3>Conclusions</h3><div>moDCs exhibit limited potential as osteoclast precursors under inflammatory conditions. Comparatively, GM-CSF (+ TNF-α)-induced progenitors represent a more viable inflammatory osteoclast precursor population. Overall, our results provide insights into osteoclast heterogeneity and RA-associated bone destruction mechanisms.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"27 ","pages":"Article 101886"},"PeriodicalIF":2.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145525775","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":"Fabric–elasticity relationships of femoral head trabecular bone are similar in Type 2 diabetes and non-diabetic individuals","authors":"Mathieu Simon ,&nbsp;Sasidhar Uppuganti ,&nbsp;Jeffry S. Nyman ,&nbsp;Philippe Zysset","doi":"10.1016/j.bonr.2025.101884","DOIUrl":"10.1016/j.bonr.2025.101884","url":null,"abstract":"&lt;div&gt;&lt;div&gt;Type 2 diabetes (T2D) is a chronic disease leading to an elevated glucose level in the blood and increased fracture risk. Because T2D individuals tend to have normal to higher areal bone mineral density (aBMD) than healthy individuals, their fracture risk is often underestimated. As an alternative, high-resolution peripheral quantitative computed tomography (HR-pQCT) is an attractive tool to investigate bone morphology in vivo and estimate fracture risk. Based on HR-pQCT scans, bone strength can be estimated using micro finite element (&lt;span&gt;&lt;math&gt;&lt;mi&gt;μ&lt;/mi&gt;&lt;/math&gt;&lt;/span&gt;FE) analysis or homogenized finite element (hFE) analysis. While &lt;span&gt;&lt;math&gt;&lt;mi&gt;μ&lt;/mi&gt;&lt;/math&gt;&lt;/span&gt;FE is computationally expensive, hFE provides an accurate estimation of bone mechanical properties within reasonable efforts. However, the hFE scheme is based on relationships between the local fabric (anisotropy) and elasticity. These relationships have been shown to hold for healthy controls as well as in the case of osteogenesis imperfecta. Nevertheless, whether these relationships are also valid for T2D-diagnosed patients remains unclear. Therefore, the present work aims to compare fabric–elasticity relationships between T2D and non-diabetic controls.&lt;/div&gt;&lt;div&gt;The present study collected 56 trabecular bone cores from the femoral head of 28 T2D and 28 control donors. These cadaveric samples were scanned in a micro-CT system at an isotropic 14.8 &lt;span&gt;&lt;math&gt;&lt;mi&gt;μ&lt;/mi&gt;&lt;/math&gt;&lt;/span&gt;m voxel size. Three cubic regions of interest (ROIs) were selected in each scan. The resolution of these ROIs was coarsened by a factor of 4, mimicking clinical HR-pQCT resolution, and the ROIs were subsequently segmented. Standard morphometric parameters were computed from the segmented ROIs using medtool (v4.8; Dr. Pahr Ingenieurs e.U., Pfaffstätten, Austria). Additionally, their fabric tensor and their apparent stiffness tensors were computed. The ROIs were compared between T2D and control regarding their morphometric and mechanical properties. Finally, ROIs were matched between T2D and control for bone volume fraction (&lt;span&gt;&lt;math&gt;&lt;mi&gt;ρ&lt;/mi&gt;&lt;/math&gt;&lt;/span&gt;) and degree of anisotropy (DA). The matched dataset allowed the comparison of fabric–elasticity relationships between T2D and control samples.&lt;/div&gt;&lt;div&gt;No significant difference was observed between T2D and control samples, both regarding their morphology and their mechanical properties. Specifically, fabric–elasticity relationships were shown to hold for both the control and the T2D groups. A comparison of the resulting exponents related to &lt;span&gt;&lt;math&gt;&lt;mi&gt;ρ&lt;/mi&gt;&lt;/math&gt;&lt;/span&gt; and DA has highlighted different trends but no important difference between T2D and control samples.&lt;/div&gt;&lt;div&gt;In conclusion, trabecular bone architecture was similar between T2D and non-T2D donors. Additionally, fabric–elasticity relationships, i.e. morphology-mechanical relationships, are also similar between donors with and without diabetes. Accordingly, HR-p","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"27 ","pages":"Article 101884"},"PeriodicalIF":2.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145424383","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":"Nanostructural changes in bone quality in a mouse model of chronic kidney disease and treatment with calcitonin","authors":"E. Montagnino ,&nbsp;W. Bush ,&nbsp;J. Bustamante ,&nbsp;W. Bandara ,&nbsp;P. Jalaie ,&nbsp;M.R. Allen ,&nbsp;J.M. Wallace ,&nbsp;T. Siegmund ,&nbsp;R.K. Surowiec ,&nbsp;J.A. Howarter","doi":"10.1016/j.bonr.2025.101880","DOIUrl":"10.1016/j.bonr.2025.101880","url":null,"abstract":"<div><div>Mineral imbalances in the body from chronic kidney disease can impact bone turnover and cause cortical bone loss. Synthetic salmon calcitonin is an FDA-approved treatment for bone fragility observed in diseases such as osteoporosis, and clinical trials have demonstrated a reduction in fractures compared to untreated individuals. This study documents the effects of calcitonin on cortical bone using an in vivo mouse model of chronic kidney disease. Serum BUN and PTH are reported. Calcitonin was found to impact at a dose of 50/IU/kg/day five times a week for five weeks. MicroCT was used to evaluate bone quantity measures, such as cortical porosity, thickness, bone area, and long bone structural geometric parameters. It was found that porosity, thickness, and bone geometry are affected by disease, but not by treatment at the specified regime. Small and wide-angle x-ray scattering (SAXS and WAXS) was used to obtain the nanostructure of the mineral-collagen-water composite, including mineral dimensions, <span><math><mi>D</mi></math></span>-periodicity and collagen spacing. Data from thermogravimetric analysis (TgA) were used to quantify wt.% of the mineral, collagen, and bound water of each sample. Chronic kidney disease was found to decrease collagen spacing to increase mineral weight fractions, and to reduce loosely bound water. There were no changes from chronic kidney disease on the <span><math><mi>D</mi></math></span>-Periodicity. Treatment increased the weight percent of collagen, with no effect on other bone quality parameters.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"27 ","pages":"Article 101880"},"PeriodicalIF":2.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145358576","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":"A novel workflow for 3D imaging and spatial analysis of nerves in bone","authors":"Allison L. Horenberg ,&nbsp;Eric Z. Zeng ,&nbsp;Yunke Ren ,&nbsp;Tanishk Sinha ,&nbsp;Emith Uyanwatte ,&nbsp;Melia Matthews ,&nbsp;Erica L. Scheller ,&nbsp;Karl J. Lewis ,&nbsp;Arvind P. Pathak ,&nbsp;Warren L. Grayson","doi":"10.1016/j.bonr.2025.101881","DOIUrl":"10.1016/j.bonr.2025.101881","url":null,"abstract":"<div><div>Peripheral sensory and sympathetic nerves innervating bony tissues are of interest for their role in modulating bone function and responding to physiologic stimuli. However, due to their filamentous structure and small diameter, peripheral nerves are difficult to visualize and characterize in dense tissues such as bone. Recent advances in imaging have resulted in novel techniques to reconstruct the 3D bone microenvironment following fluorescent staining, using methods such as whole-mount immunostaining, tissue clearing, and lightsheet microscopy (LSM). While these methods have significantly improved visualization of peripheral nerves within the bony skeleton, current practices in skeletal nerve segmentation rely on manual tracing methods that are both subjective and time consuming. Further, due to excess background signal and moderate off-target staining of skeletal nerves, traditional methods for nerve segmentation remain inadequate for effective quantification. Here, we describe a methods-focused workflow for 3D imaging and spatial analysis of nerves in bone that consists of combining LSM with nerve segmentation using the Ilastik® open-source software. First, LSM was used to acquire high-resolution 3D images of nerves in uninjured and injured murine calvaria. Next, we employed Ilastik® to generate accurate segmentations of peripheral nerves in bone. This approach reduced the need for manual segmentation and overcame the limitations of conventional segmentation methods. We then demonstrated the utility of this workflow as a broadly applicable tool, by performing Ilastik®-based segmentation for three distinct skeletal bone contexts (i.e. use cases) with varied bone samples, tissue clearing, processing protocols, inflammatory states, and imaging modalities. Collectively, this workflow enabled the characterization of spatial nerve patterning in bone and has the potential to provide novel insights into spatially regulated phenomena in bone homeostasis, injury, and disease.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"27 ","pages":"Article 101881"},"PeriodicalIF":2.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145263212","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":"Cyclin-dependent kinase inhibitor-1 deficiency enhances bone destruction in a mouse model of arthritis","authors":"Kensuke Wada ,&nbsp;Shinya Hayashi ,&nbsp;Yuma Onoi ,&nbsp;Shotaro Tachibana ,&nbsp;Yoshihito Suda ,&nbsp;Akira Saito ,&nbsp;Takuma Maeda ,&nbsp;Shotaro Araki ,&nbsp;Kohei Motono ,&nbsp;Tomoyuki Kamenaga ,&nbsp;Masanori Tsubosaka ,&nbsp;Yuichi Kuroda ,&nbsp;Naoki Nakano ,&nbsp;Tomoyuki Matsumoto ,&nbsp;Ryosuke Kuroda","doi":"10.1016/j.bonr.2025.101892","DOIUrl":"10.1016/j.bonr.2025.101892","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA) causes bone destruction by activating inflammatory cytokines and osteoclasts. Cyclin-dependent kinase inhibitor 1 (p21), a cell cycle regulator, may influence this process; however, its role remains unclear. Therefore, we investigated the effect and potential mechanisms of p21 deficiency in bone loss in a mouse model of arthritis. Collagen antibody-induced arthritis (CAIA) was established in p21 knockout (<em>p21</em>^{<em>−/−</em>}) and wild-type mice. Bone destruction was analyzed using histology, micro-computed tomography, and bone strength testing; osteoclast formation and activity were evaluated using tartrate-resistant acid phosphatase (TRAP) staining and immunohistochemistry for cathepsin K. The expression of inflammatory cytokines and osteoclast-related genes was examined using immunohistochemistry and real-time polymerase chain reaction, respectively. <em>p21</em>^<em>−</em><em>/</em>^<em>−</em> mice exhibited greater bone destruction and lower bone strength than wild-type mice. Additionally, TRAP and cathepsin K staining revealed significantly higher osteoclast count in <em>p21</em>^<em>−</em><em>/</em>^<em>−</em> mice. Interleukin (IL)-6, IL-1β, tumor necrosis factor-alpha (TNF-α), and phosphorylated signal transducer and activator of transcription 3 (STAT3) levels were considerably higher in bone tissues of <em>p21</em>^<em>−</em><em>/</em>^<em>−</em> mice than in those of wild-type mice. In vitro osteoclast differentiation in bone marrow macrophages (BMMs) was examined after IL-6 stimulation; osteoclast differentiation and osteoclast marker gene expression were significantly enhanced in <em>p21</em>^{<em>−/−</em>} BMMs. Western blotting confirmed increased STAT3 phosphorylation in <em>p21</em>^{<em>−/−</em>} BMMs; IL-6 treatment further amplified osteoclastogenesis in <em>p21</em>^{<em>−/−</em>} BMMs. In conclusion, p21 deficiency exacerbates bone destruction in arthritis by promoting osteoclast differentiation and inflammatory cytokine expression via the IL-6/STAT3 pathway. Targeting p21 may offer therapeutic potential for preventing arthritis-related bone loss, such as in RA.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"27 ","pages":"Article 101892"},"PeriodicalIF":2.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145690497","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":"Scavenging methylglyoxal improves bone quality and defect healing in diabetic mice","authors":"Toshifumi Hikichi ,&nbsp;Kumi Kimura ,&nbsp;Seiichi Munesue ,&nbsp;Yu Oshima ,&nbsp;Ai Harashima ,&nbsp;Tomo Hamada ,&nbsp;Kanu Shimokawa ,&nbsp;Yuki Fushitani ,&nbsp;Hisanori Goto ,&nbsp;Hiroyuki Tsuchiya ,&nbsp;Satoru Demura ,&nbsp;Hidenori Matsubara ,&nbsp;Yasuhiko Yamamoto","doi":"10.1016/j.bonr.2025.101883","DOIUrl":"10.1016/j.bonr.2025.101883","url":null,"abstract":"<div><div>Hyperglycemia in diabetes leads to the formation of methylglyoxal (MG) and accumulation of advanced glycation end-products (AGEs). We previously reported that exogenous MG exposure deteriorated osteoblastic differentiation in vitro and diabetic mice showed delayed bone defect healing along with elevated MG-derived AGE levels. However, whether endogenously formed MG is involved in impaired bone repair and remodeling in diabetes remains unclear. In this study, we investigated the effects of hyperglycemia-induced MG formation on bone quality and defect healing in mice. Using a synthetic MG probe [Ir(ppy)₂(DA-phen)], we found that endogenous MG formation deteriorated osteoblastic and osteoclastic differentiation under hyperglycemic conditions in cultured cells. In the bone defect site of streptozotocin (STZ)-induced diabetic mice, along with impaired defect healing, we observed elevated endogenous MG levels and downregulation of alkaline phosphatase (ALP) compared with that in non-diabetic control mice; however, these alterations were alleviated by managing blood glucose levels through insulin supplementation. Furthermore, treatment with pyridoxamine (PM), an MG scavenger, ameliorated these impairments by suppressing MG elevation and upregulating the expression of osteocalcin, osteoprotegerin, and osteoclast-associated receptor genes without improving the diabetic status. These findings suggest that endogenously formed MG is detrimental to hyperglycemia-related delayed bone defect healing in type 1 diabetes mellitus (T1DM). Collectively, this study suggests that MG scavenging by PM and suppression of MG formation by glycemic control are potential therapeutic strategies for T1DM-associated bone disorders.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"27 ","pages":"Article 101883"},"PeriodicalIF":2.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145473900","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":"Increased fatty acid availability improves the osteo-anabolic effects of intermittent parathyroid hormone (iPTH) in murine models","authors":"Santosh Thapa ,&nbsp;Jake Newberry ,&nbsp;S.V.V.S. Ravi Mangu ,&nbsp;Ron C.M. Helderman ,&nbsp;Ananya Nandy ,&nbsp;Cameron Fawcett ,&nbsp;Sasidhar Uppuganti ,&nbsp;Jeffry S. Nyman ,&nbsp;Elizabeth Rendina-Ruedy","doi":"10.1016/j.bonr.2025.101887","DOIUrl":"10.1016/j.bonr.2025.101887","url":null,"abstract":"<div><div>Osteoporosis is a major public health problem which results in reduced bone mineral density (BMD) and increased fracture risk. Osteoporosis-related fractures often lead to multiple comorbidities which can significantly reduce longevity and diminish one's quality of life. While anabolic agents that increase bone formation, such as parathyroid hormone (PTH), have aided in the management of osteoporosis, patients still experience adverse side-effects along with variations in therapeutic response. Therefore, continued development of refined therapeutic interventions as well as improving efficacy is necessary. Relative to this, the current experiments report on the ability to harness PTH's impact to modulate osteoblast bioenergetic capacity to promote bone formation by supplying fatty acid substrates to meet this energetic demand. To accomplish this, mice were fed a moderately ‘high’ fat diet (2.5×) or control fat, as to not induce metabolic perturbations, while treating with or without PTH for 4 weeks. This dietary regimen resulted in improved bone parameters in mice fed the high fat diet compared to control diet. To directly test the contribution of increased exogenous fatty acid substrates during PTH treatment, we next introduced oleic acid simultaneous to PTH treatment for 4 weeks, and again showed improved skeletal parameters compared to the vehicle-control treated mice. These data support previous publications that demonstrate the osteoanabolic responsiveness of osteoblasts to PTH requires fatty acid substrates. These data further expand on these findings, by providing evidence that PTH efficacy can be improved by supplying exogenous fatty acid substrates, either by dietary or direct interventions.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"27 ","pages":"Article 101887"},"PeriodicalIF":2.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145525773","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 effects of geranylgeranyl diphosphate synthase inhibitor treatment on osteoblast biology and application in a conditioned media model of myeloma bone disease","authors":"Molly E. Muehlebach ,&nbsp;Sarah A. Holstein","doi":"10.1016/j.bonr.2025.101874","DOIUrl":"10.1016/j.bonr.2025.101874","url":null,"abstract":"<div><div>Myeloma bone disease (MBD) is characterized by tumor-induced osteoclast activation with concomitant suppression of osteoblast activity. Nitrogen bisphosphonates (NBPs), including zoledronic acid (ZA), are a mainstay of MBD treatment, due to their anti-osteoclastic effects secondary to high bone affinity and indirect disruption of protein geranylgeranylation through inhibition of farnesyl diphosphate synthase. The development of geranylgeranyl diphosphate synthase (GGDPS) inhibitors (GGSIs) represents a more selective means of targeting geranylgeranylation. The GGSI RAM2061 has direct anti-myeloma activity in vitro and in vivo, achieves both systemic and skeletal distribution, and has anti-osteoclastic activity. However, the effects of this novel therapy on osteoblast activity or in a setting that recapitulates the MBD milieu have yet to be explored. Exposure to RAM2061 or ZA during MC3T3-E1 differentiation resulted in impairment in osteoblast function, including alkaline phosphatase and mineralization activity, however minimal effects were observed in differentiated MC3T3-E1 cells that were subsequently exposed to drug. To evaluate the impact of RAM2061 on osteoblast or osteoclast activity under MBD-like conditions, JJN3 myeloma cell conditioned media (CM) was collected and added to bone cell cultures in order to simulate osteoclast-activating or osteoblast-inhibitory MBD microenvironments. These studies determined that RAM2061 maintains anti-resorptive effects and osteoblast inhibitory effects in undifferentiated precursors while in the presence of JJN3 CM. However, no appreciable effects were detected in osteoblasts exposed to drug post-differentiation. Overall, these studies contribute to the mechanistic understanding of NBP and GGSI effects in the bone and provide support for the continued investigation of GGSIs in MBD.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"27 ","pages":"Article 101874"},"PeriodicalIF":2.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145010897","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":"High-fat diet induced obesity and anti-activin receptor antibody: Effects on bone properties in mice","authors":"Frederik Duch Bromer ,&nbsp;Andreas Lodberg ,&nbsp;Lykke Sylow ,&nbsp;Michala Carlsson ,&nbsp;Christian Brix Folsted Andersen ,&nbsp;Jesper Skovhus Thomsen ,&nbsp;Annemarie Brüel","doi":"10.1016/j.bonr.2025.101878","DOIUrl":"10.1016/j.bonr.2025.101878","url":null,"abstract":"<div><h3>Aim</h3><div>Weight-loss therapy often results in an unintended loss of muscle and bone mass. Inhibitors of the activin receptor signaling pathway, such as bimagrumab, an anti-activin receptor antibody (αActRIIA/IIB ab), are under investigation to counteract weight-loss induced muscle loss, but their skeletal effects in obesity remain unclear. This study investigates αActRIIA/IIB ab on bone in mice exposed to a high-fat diet (HFD) model of obesity or standard chow.</div></div><div><h3>Materials and methods</h3><div>Male C57BL/6 J mice were stratified into four groups (<em>n</em> = 10/group, standard chow or HFD for 10 weeks ± αActRIIA/IIB ab). αActRIIA/IIB ab (10 mg/kg) was administered twice weekly during the final three weeks. The femur and vertebral body were assessed using DEXA, μCT, mechanical testing, and histomorphometry.</div></div><div><h3>Results</h3><div>HFD did not affect bone density, microstructure, or strength but reduced histological bone formation markers. In standard chow mice, αActRIIA/IIB ab increased trabecular bone volume fraction (BV/TV) and volumetric bone mineral density (vBMD) by 36 %. In HFD mice, the effect of αActRIIA/IIB ab was less pronounced but still increased BV/TV (+16 %) and vBMD (+13 %). For cortical bone, μCT parameters remained largely unaffected by αActRIIA/IIB ab, while the treatment increased periosteal mineralizing bone surfaces in standard chow mice (+217 %), but not in HFD mice.</div></div><div><h3>Conclusions</h3><div>αActRIIA/IIB ab enhanced trabecular bone properties in standard chow-fed mice, but its anabolic effects were blunted in HFD-fed mice. Furthermore, αActRIIA/IIB ab improved cortical histological bone formation markers, while morphology remained unaffected, suggesting a site- or time-specific difference. Thus, αActRIIA/IIB ab holds potential for mitigating weight-loss-associated bone deterioration.</div></div>","PeriodicalId":9043,"journal":{"name":"Bone Reports","volume":"27 ","pages":"Article 101878"},"PeriodicalIF":2.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145118986","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}