Skeletal Integrity Research Articles

Modern approach to bone comorbidity in prolactinoma.

Prolactinomas account for more than half of pituitary adenomas, and besides their clinical impact on fertility and gonadal function, they lead to detrimental effects on bone. Patients with prolactinoma are prone to deterioration of bone structure caused not only by prolactin (PRL) induced hypogonadism but also by its direct actions on bone cells and calcium metabolism. However, clinical studies have shown inconsistent evidence regarding whether PRL could have a deleterious effect independently from gonadal insufficiency on skeletal integrity. Seminal studies from our group reported an increased prevalence of vertebral fractures (VFs) in both female and male patients with prolactinoma. Treatment of prolactinoma with dopamine agonists can restore gonadal function and improve bone mineral density. Since the presence of VFs may be related to more aggressive disease, bone comorbidities in prolactinoma should be managed by a multidisciplinary team in line with the recent concept of 'pituitary tumors centers of excellence'. The review aims to evaluate the mechanism of PRL actions on bone, as well as to provide practical indications for a modern approach to the management of skeletal complications of patients with prolactin-secreting adenoma considering different clinical characteristics and outcomes.

Lipin1 as a therapeutic target for respiratory insufficiency of duchenne muscular dystrophy

In Duchenne muscular dystrophy (DMD), diaphragm muscle dysfunction results in respiratory insufficiency which is a leading cause of death in patients. Mutations to the dystrophin gene result in myocyte membrane instability, contributing to the structural deterioration of the diaphragm muscle tissues. With previous works suggesting the importance of lipin1 for maintaining skeletal muscle membrane integrity, we explored the roles of lipin1 in the dystrophic diaphragm. We found that the protein expression levels of lipin1 were reduced by 60% in the dystrophic diaphragm. While further knockdown of lipin1 in the dystrophic diaphragm leads to increased necroptosis, restoration of lipin1 in the dystrophic diaphragm results in reduced inflammation and fibrosis, decreased myofiber death, and improved respiratory function. Our results demonstrated that lipin1 restoration improved respiratory function by enhancing membrane integrity and suggested that lipin1 could be a potential therapeutic target for preventing respiratory insufficiency and respiratory failure in DMD. Continued investigation is required to better understand the mechanisms behind these findings, and to determine the role of lipin1 in maintaining muscle membrane stability.

Trajectory-centric framework TrajAtlas reveals multi-scale differentiation heterogeneity among cells, genes, and gene modules in osteogenesis.

Osteoblasts, the key cells responsible for bone formation and the maintenance of skeletal integrity, originate from a diverse array of progenitor cells. However, the mechanisms underlying osteoblast differentiation from these multiple osteoprogenitors remain poorly understood. To address this knowledge gap, we developed a comprehensive framework to investigate osteoblast differentiation at multiple scales, encompassing cells, genes, and gene modules. We constructed a reference atlas focused on differentiation, which incorporates various osteoprogenitors and provides a seven-level cellular taxonomy. To reconstruct the differentiation process, we developed a model that identifies the transcription factors and pathways involved in differentiation from different osteoprogenitors. Acknowledging that covariates such as age and tissue type can influence differentiation, we created an algorithm to detect differentially expressed genes throughout the differentiation process. Additionally, we implemented methods to identify conserved pseudotemporal gene modules across multiple samples. Overall, our framework systematically addresses the heterogeneity observed during osteoblast differentiation from diverse sources, offering novel insights into the complexities of bone formation and serving as a valuable resource for understanding osteogenesis.

Pdk3's role in RANKL-induced osteoclast differentiation: insights from a bone marrow macrophage model.

Osteoporosis (OP) is a chronic disease characterized by decreased bone mass, loss of skeletal structural integrity and increased susceptibility to fracture. Available studies have shown that the pyruvate dehydrogenase kinase (PDK) family is associated with osteoclastogenesis and bone loss, but the specific role of Pdk3 in bone pathology has not been systematically investigated. A cell OP model was established in receptor activator for nuclear factor-κB Ligand (RANKL)-induced bone marrow macrophages (BMMs). Hereafter, the expression levels of Pdk3 and osteoclastogenesis feature genes including nuclear factor of activated T cells 1 (Nfatc1), Cathepsin K (Ctsk), osteoclast associated Ig-like receptor (Oscar) in BMMs-derived osteoclasts were examined based on real-time quantitative PCR and western blotting methods. Further, the phosphorylation of ERK, P65 and JAK/STAT and their correlation was Pdk3 was gauged. In particular, changes in the activity of these signaling pathways were observed by silencing experiments of the Pdk3 gene (using small interfering RNA). Finally, the effects of Pdk3 gene silencing on signaling pathway activity, osteoclastogenesis, and related inflammatory and apoptotic indicators were observed by transfection with PDK3-specific siRNA. Following RANKL exposure, the levels of Pdk3 and osteoclastogenesis feature genes were all elevated, and a positive correlation between Pdk3 and osteoclastogenesis feature genes was seen. Meanwhile, ERK, P65 and JAK/STAT phosphorylation was increased by RANKL, and Pdk3 was confirmed to be positively correlated with the phosphorylation of ERK, P65 and JAK/STAT. Additionally, in RANKL-exposed osteoclasts, Pdk3 knockdown diminished the phosphorylation of ERK, P65 and JAK/STAT, reduced the expressions of osteoclastogenesis feature genes. Importantly, knockdown of Pdk3 also reduced the expression of inflammatory cytokines and resulted in elevated levels of Bax and Casp3 expression, as well as downregulation of Bcl2 expression. This study reveals for the first time the role of Pdk3 in RANKL-induced osteoclastogenesis and OP. These findings provide a foundation for future studies on the role of Pdk3 in other bone diseases and provide new ideas for the development of OP therapeutics targeting Pdk3.

Maternal high-fat high-sugar diet impairs bone quality and strength but not cartilage in aging mice.

Osteoarthritis (OA) is a prevalent aging disorder of synovial joints and recent work suggests that a parental high-fat diet increases OA severity following joint injury in offspring. We hypothesized that a maternal high-fat high-sugar (HFHS) diet would promote spontaneous osteoarthritis-related cartilage and bone changes in 1-year-old offspring. Female C57BL/6 J mice were placed on either a chow control or HFHS diet for 6 weeks before mating to a chow-fed C57BL/6 J male and maintained on their assigned diets throughout pregnancy and lactation. Male and female offspring were weaned onto a chow diet, raised to 1 year of age, and evaluated for cartilage and bone changes indicative of OA. However, offspring did not show early signs of OA as measured by histological Mankin scoring, mechanical testing of the pericellular matrix, histological synovitis scoring, or subchondral bone thickening as measured by microcomputed Tomography. On the other hand, male offspring from HFHS-fed dams had reduced trabecular bone quality in the tibial metaphysis and decreased cortical thickness. Although maternal HFHS diet did not impact trabecular or cortical bone quality in tibias of female offspring, the radii of these animals had decreased cortical thickness, increased medullary area, and impaired breaking strength compared to those of control-fed dams. Finally, we evaluated bone quality and strength in male and female F2 offspring and found that the grandmaternal diet modestly impacted radial bone geometry but not strength. Together these results suggest that maternal HFHS diet impairs F1 offspring skeletal integrity in a sex and bone site-specific manner.

SOST/Sclerostin impairs the osteogenesis and angiogesis in glucocorticoid-associated osteonecrosis of femoral head.

Glucocorticoid-associated osteonecrosis of the femoral head (GA-ONFH) is a progressive bone disorder which frequently results in femoral head collapse and hip joint dysfunction. Sclerostin (SOST) is principally secreted by osteocytes in bone and plays an important role in bone homeostasis and homeostasis of skeletal integrity. Our previous study reported that short-term use of glucocorticoid increased serum sclerostin levels. Here this study is aimed to identify whether sclerostin played an essential role in the occurrence and development of GA-ONFH. Glucocorticoid-induced osteonecrosis of femoral head (ARCO stage II) samples were collected and sclerostin staining was conducted. Osteocyte cell line Ocy454, MC3T3-E1 and endothelial cells was used. MC3T3-E1 or endothelial cells were co-cultured with Ocy454 or SOST-silencing Ocy454 in presence of dexamethasone to mimic the crosstalk of various cells in the bone niche. GA-ONFH rat model and SOST knockout model was built to better understand the phenomenon in vivo. Sclerostin was highly concentrated in osteonecrosis patient sample in the necrotic area. Co-culture with osteocytes aggravated the inhibition of dexamethasone on MC3T3-E1 and endothelial cells. Sclerostin derived from osteocytes impaired osteogenesis and angiogenesis via inhibiting the Wnt pathway. In GA-ONFH rat model, SOST knockout ameliorated the incidence of osteonecrosis and improved bone metabolism compared with the wild type group through histological, immunohistochemical and bone metabolic analyses. Sclerostin contribute to pathologic process of GA-ONFH by impairing osteogenesis and angiogenesis.

Knockout of rbm24a and rbm24b genes in zebrafish impairs skeletal and cardiac muscle integrity and function during development.

Skeletal and cardiac muscles are contractile tissues whose development and function are dependent on genetic programs that must be precisely orchestrated in time and space. In addition to transcription factors, RNA-binding proteins tightly regulate gene expression by controlling the fate of RNA transcripts, thus specific proteins levels within the cell. Rbm24 has been identified as a key player of myogenesis and cardiomyogenesis in several vertebrates, by controlling various aspects of post-transcriptional regulation, including pre-mRNA alternative splicing and mRNA stabilization. In zebrafish, knockdown of rbm24a or rbm24b also causes skeletal and cardiac muscle phenotypes, but how their combined loss affects muscle integrity and function remains elusive. By genome editing, we have generated rbm24a and rbm24b single mutants as well as double mutants. Structural analyses indicate that homozygous rbm24a and rbm24b double mutants exhibit severe somitic muscle and cardiac phenotypes, although rbm24b single mutants are obviously normal. We further show that the loss of rbm24a and rbm24b disrupts sarcomere organization, impairing functional contractility and motility of skeletal and cardiac muscles. The rbm24 mutant zebrafish represents a new genetic tool for in-depth studies of Rbm24-mediated post-transcriptional regulation of skeletal and cardiac muscle development, disease and regeneration.

Psoas muscle cross sectional area relates to bone density and microarchitecture in candidates for spine fusion surgery

Prior studies demonstrate that muscle and bone health are integrally related, and both independently impact orthopedic surgery outcomes. However, relationships between bone density, in vivo microarchitecture, and muscle area have not been previously investigated in orthopedic surgery patients. This study assessed associations between psoas cross sectional area (CSA), bone mineral density (BMD), and microstructure in a cohort undergoing spine fusion. Pre-operatively, bilateral psoas CSA was measured on axial lumbar spine CT in the L3-L4 disc space. To adjust for body size, Psoas Muscle Index (PMI) was calculated (CSA divided by the square of patient height). High resolution peripheral quantitative CT (HR-pQCT, XtremeCT2) assessed volumetric BMD (vBMD), cortical (Ct) and trabecular (Tb) microarchitecture at the distal radius and tibia. Areal BMD (aBMD) was measured by DXA at the lumbar spine (LS), total hip (TH), femoral neck (FN), and the 1/3 radius (1/3R). Pearson correlations related psoas CSA and bone imaging parameters before and after correcting for height and weight. Among 88 patients included, mean age was 63 ± 12 years, BMI was 28 ± 7 kg/m2, 47 (53 %) were female. Larger psoas CSA was associated with higher vBMD, greater Ct thickness and better Tb microarchitecture (higher Tb number and lower Tb separation) at the tibia and radius. Larger psoas CSA was also associated with greater aBMD at TH and FN bilaterally and 1/3R (r 0.33 to 0.61; p < 0.002 for all comparisons). Psoas CSA was not associated with aBMD at the LS. Similar results were observed when relating PMI, and adjusting for age, height and weight to HR-pQCT and DXA measurements. Investigation of subgroups by sex demonstrated that relationships were similar magnitude among women but not the men. Patients who underwent primary compared to revision spine surgery had similar associations. Our results demonstrate a link between psoas muscle size and peripheral bone microarchitecture among patients undergoing posterior lumbar spinal fusion. Given the importance of both muscle and skeletal integrity to the success of spine surgery, further study regarding the associations between measurements of psoas muscle, bone microarchitecture, and surgical outcomes is warranted.

The Bone, Exercise, Alendronate, and Caloric Restriction (BEACON) trial design and methods

BackgroundAmong older adults living with obesity, intentional weight loss (WL) improves prognosis of many comorbidities. However, concomitant decline in bone mineral density (BMD) limits overall benefit of WL by increasing osteoporotic fracture risk. Identification of intervention strategies to maximize body fat loss, while minimizing harm to the musculoskeletal system, is an important area of clinical research. The main objective of the Bone, Exercise, Alendronate, and Caloric Restriction (BEACON) trial (NCT05764733) is to compare the independent and combined effects of a 12-month intervention of resistance training (RT) plus bone-loading exercises and bisphosphonate use on dietary WL-associated bone loss among 308 older (≥60 years) adults living with an indication for WL and bisphosphonate use. MethodsAll participants will receive the same group-mediated dietary intervention targeting 8–10 % WL and be randomized to one of four groups: no RT and placebo capsules (NoRT+PL); progressive RT plus bone-loading exercises and placebo capsules (RT++PL); no RT and oral bisphosphonate (70 mg weekly oral alendronate; NoRT+BIS); or progressive RT plus bone-loading exercises and oral bisphosphonate (RT++BIS). Total hip areal (a)BMD measured via dual-energy x-ray absorptiometry (DXA) is the primary, powered study outcome. Secondary skeletal outcome measures include femoral neck and lumbar spine aBMD, high resolution peripheral quantitative computed tomography (HRpQCT) bone assessments of the radius and tibia, and biomarkers of bone turnover. DiscussionBEACON will address an understudied, yet important, clinical research question by studying the independent and combined effects of two scalable intervention strategies aimed at optimizing skeletal integrity in older adults undergoing WL.Clinical Trials Registration: NCT05764733

Glutaminolysis provides nucleotides and amino acids to regulate osteoclast differentiation in mice

Osteoclasts are bone resorbing cells that are essential to maintain skeletal integrity and function. While many of the growth factors and molecular signals that govern osteoclastogenesis are well studied, how the metabolome changes during osteoclastogenesis is unknown. Using a multifaceted approach, we identified a metabolomic signature of osteoclast differentiation consisting of increased amino acid and nucleotide metabolism. Maintenance of the osteoclast metabolic signature is governed by elevated glutaminolysis. Mechanistically, glutaminolysis provides amino acids and nucleotides which are essential for osteoclast differentiation and bone resorption in vitro. Genetic experiments in mice found that glutaminolysis is essential for osteoclastogenesis and bone resorption in vivo. Highlighting the therapeutic implications of these findings, inhibiting glutaminolysis using CB-839 prevented ovariectomy induced bone loss in mice. Collectively, our data provide strong genetic and pharmacological evidence that glutaminolysis is essential to regulate osteoclast metabolism, promote osteoclastogenesis and modulate bone resorption in mice.

Cellular mechanisms of acute rhabdomyolysis in inherited metabolic diseases.

Acute rhabdomyolysis (RM) constitutes a life-threatening emergency resulting from the (acute) breakdown of skeletal myofibers, characterized by a plasma creatine kinase (CK) level exceeding 1000 IU/L in response to a precipitating factor. Genetic predisposition, particularly inherited metabolic diseases, often underlie RM, contributing to recurrent episodes. Both sporadic and congenital forms of RM share common triggers. Considering the skeletal muscle's urgent need to rapidly adjust to environmental cues, sustaining sufficient energy levels and functional autophagy and mitophagy processes are vital for its preservation and response to stressors. Crucially, the composition of membrane lipids, along with lipid and calcium transport, and the availability of adenosine triphosphate (ATP), influence membrane biophysical properties, membrane curvature in skeletal muscle, calcium channel signaling regulation, and determine the characteristics of autophagic organelles. Consequently, a genetic defect involving ATP depletion, aberrant calcium release, abnormal lipid metabolism and/or lipid or calcium transport, and/or impaired anterograde trafficking may disrupt autophagy resulting in RM. The complex composition of lipid membranes also alters Toll-like receptor signaling and viral replication. In response, infections, recognized triggers of RM, stimulate increased levels of inflammatory cytokines, affecting skeletal muscle integrity, energy metabolism, and cellular trafficking, while elevated temperatures can reduce the activity of thermolabile enzymes. Overall, several mechanisms can account for RMs and may be associated in the same disease-causing RM.

The Pediatric Ankle: Normal Variations and Maturation-Dependent Pathology.

The pediatric ankle can present a broad range of normal variation and pathology unique to certain stages of development. Understanding the expected age ranges of ossification and fusion about the ankle is essential to provide accurate diagnoses regarding skeletal integrity. This conclusion has been well characterized radiographically and is supported by cadaveric research.The range of appearances on magnetic resonance imaging has also been well described. Knowledge about the structure of the periosteum and perichondrium aids in image interpretation as well as explaining typical injury patterns. The expected appearance of the physis and regional bone marrow signal is also of utmost importance.Ultrasonography is a valuable tool in pediatric musculoskeletal imaging but is limited when there is concern for intra-articular pathology. Computed tomography tends to be reserved for preoperative evaluation. We describe normal variation and maturation-dependent pathology of the pediatric ankle with an emphasis on imaging considerations.

Plasma C-terminal agrin fragment concentrations across adulthood: Reference values and associations with skeletal muscle health.

Increasing interest surrounds the utility of blood-based biomarkers for diagnosing sarcopenia. C-terminal agrin fragment (CAF), a marker of neuromuscular junction stability, is amongst the most promising candidates; however, a dearth of reference data impedes the incorporation of its use in public health settings. This study aimed to establish reference values for plasma CAF concentrations across adulthood in a large, well-characterized cohort of healthy adults; and comprehensively examine the association between plasma CAF levels and skeletal muscle health. One thousand people aged between 18 and 87years took part in this study (mean age=50.4years; 51% females). Body composition and muscle strength were examined using DXA and hand dynamometry. Plasma CAF concentrations were measured, in duplicate, using commercially available ELISA kits. Sarcopenia and individual sarcopenia signatures [low skeletal muscle index (SMI) only/low grip strength only] were classified using the EWGSOP2 algorithm. Detailed reference CAF values, according to sex and age, are presented. A significant but modest age-related increase in plasma CAF concentration was observed (P=0.018). Across adulthood, CAF concentrations were negatively associated with grip strength and SMI (both P<0.001). In people ≥50years old, CAF concentrations were 22.6% higher in those with sarcopenia (P<0.001), 11.3% higher in those with low SMI (P=0.006) and 9.6% higher in those with low grip strength (P=0.0034), compared with controls. People in the highest CAF concentration quartile, had 3.25 greater odds for sarcopenia (95% CI=1.41-7.49, P=0.005), 2.76 greater odds for low SMI (95% CI=1.24-5.22, P=0.012), and 2.56 greater odds for low grip strength (95% CI=1.07-5.57, P=0.037), compared with those in the lowest quartile. People with a CAF Z-score ≥2 had 9.52 greater odds for sarcopenia (95% CI=3.01-30.05, P<0.001) compared with a Z-score <1. Plasma CAF concentration had an acceptable level of diagnostic accuracy for sarcopenia (AUC=0.772, 95% CI=0.733-0.807, P<0.001). The reference values presented herein may guide the clinical interpretation of circulating CAF and help identify people at risk of poor skeletal muscle outcomes for inclusion in therapeutic interventions. Our findings add clarity to existing data, demonstrating a robust relationship between circulating CAF and skeletal muscle integrity in the largest adult cohort to date, and support the use of CAF as an accessible, cost-effective screening tool for sarcopenia. However, further research into the prognostic utility of plasma CAF, and the establishment of normative data from other populations, are urgently needed if routine CAF screening is to be embedded into public healthcare settings.

Advances on T cell immunity in bone remodeling and bone regeneration.

Bone remodeling and bone regeneration are essential for preserving skeletal integrity and maintaining mineral homeostasis. T cells, as key members of adaptive immunity, play a pivotal role in bone remodeling and bone regeneration by producing a range of cytokines and growth factors. In the physiological state, T cells are involved in the maintenance of bone homeostasis through interactions with mesenchymal stem cells, osteoblasts, and osteoclasts. In pathological states, T cells participate in the pathological process of different types of osteoporosis through interaction with estrogen, glucocorticoids, and parathyroid hormone. During fracture healing for post-injury repair, T cells play different roles during the inflammatory hematoma phase, the bone callus formation phase and the bone remodeling phase. Targeting T cells thus emerges as a potential strategy for regulating bone homeostasis. This article reviews the research progress on related mechanisms of T cells immunity involved in bone remodeling and bone regeneration, with a view to providing a scientific basis for targeting T cells to regulate bone remodeling and bone regeneration.

Hydrolyzed egg yolk powder promotes bone growth and development in rats: A multidimensional mechanistic study

Given the growing worldwide focus on bone health, exploring safe and effective interventions to maintain skeletal integrity is imperative. This study involved intragastrically administering hydrolyzed egg yolk powder (HEYP) to 3-week-old Sprague‒Dawley (SD) rats over a period of six weeks. The effects of HEYP on bone growth and the underlying mechanisms were comprehensively investigated by evaluating known bone growth parameters, bone microstructural features, serum biochemical parameters, the metabolome, and the gut microbiome. HEYP administration significantly increased longitudinal bone growth while concurrently increasing the serum levels of osteogenic growth factors. Subsequent metabolomic analyses revealed significant alterations in the serum levels of metabolites associated with bone metabolism, highlighting the profound impact of HEYP on amino acid metabolism. Additionally, gut microbiome analyses revealed HEYP-induced changes in the gut microbiota (GM), identifying key bacterial genera, including Blautia, Parasutterella, Marvinbryantia and Prevotella, that were potentially beneficial for bone formation and linked to bone growth. Correlation analyses further highlighted associations between significantly altered serum metabolites, distinct bacterial genera, and bone growth-related parameters. These findings emphasized that HEYP might promote bone growth through various pathways, offering insights into the potential development and application of functional foods that promote bone health and potentially aid in osteoporosis prevention.

Impact of the SIK3 pathway inhibition on osteoclast differentiation via oxidative phosphorylation.

Maintenance of bone homeostasis and the balance between bone resorption and formation are crucial for maintaining skeletal integrity. This study sought to investigate the role of salt-inducible kinase 3 (SIK3), a key regulator in cellular energy metabolism, during the differentiation of osteoclasts. Despite osteoclasts being high energy-consuming cells essential for breaking down mineralized bone tissue, the specific function of SIK3 in this process remains unclear. To address this issue, we generated osteoclast-specific SIK3 conditional knockout mice and assessed the impact of SIK3 deletion on bone homeostasis. Our findings revealed that SIK3 conditional knockout mice exhibited increased bone mass and an osteopetrosis phenotype, suggesting a pivotal role for SIK3 in bone resorption. Moreover, we assessed the impact of pterosin B, a SIK3 inhibitor, on osteoclast differentiation. The treatment with pterosin B inhibited osteoclast differentiation, reduced the numbers of multinucleated osteoclasts, and suppressed resorption activity in vitro. Gene expression analysis demonstrated that SIK3 deletion and pterosin B treatment influence a common set of genes involved in osteoclast differentiation and bone resorption. Furthermore, pterosin B treatment altered intracellular metabolism, particularly affecting key metabolic pathways, such as the tricarboxylic acid cycle and oxidative phosphorylation. These results provide valuable insights into the involvement of SIK3 in osteoclast differentiation and the molecular mechanisms underlying osteoclast function and bone diseases.

Nanofibrous Microspheres: A Biomimetic Platform for Bone Tissue Regeneration.

Bone, a fundamental constituent of the human body, is a vital scaffold for support, protection, and locomotion, underscoring its pivotal role in maintaining skeletal integrity and overall functionality. However, factors such as trauma, disease, or aging can compromise bone structure, necessitating effective strategies for regeneration. Traditional approaches often lack biomimetic environments conducive to efficient tissue repair. Nanofibrous microspheres (NFMS) present a promising biomimetic platform for bone regeneration by mimicking the native extracellular matrix architecture. Through optimized fabrication techniques and the incorporation of active biomolecular components, NFMS can precisely replicate the nanostructure and biochemical cues essential for osteogenesis promotion. Furthermore, NFMS exhibit versatile properties, including tunable morphology, mechanical strength, and controlled release kinetics, augmenting their suitability for tailored bone tissue engineering applications. NFMS enhance cell recruitment, attachment, and proliferation, while promoting osteogenic differentiation and mineralization, thereby accelerating bone healing. This review highlights the pivotal role of NFMS in bone tissue engineering, elucidating their design principles and key attributes. By examining recent preclinical applications, we assess their current clinical status and discuss critical considerations for potential clinical translation. This review offers crucial insights for researchers at the intersection of biomaterials and tissue engineering, highlighting developments in this expanding field.

Molecular Deconvolution of Bone Marrow Adipose Tissue Interactions with Malignant Hematopoiesis: Potential for New Therapy Development.

Along with a strong impact on skeletal integrity, bone marrow adipose tissue (BMAT) is an important modulator of the adult hematopoietic system. This review will summarize the current knowledge on the causal relationship between bone marrow (BM) adipogenesis and the development and progression of hematologic malignancies. BM adipocytes (BMAds) support a number of processes promoting oncogenesis, including the evolution of clonal hematopoiesis, malignant cell survival, proliferation, angiogenesis, and chemoresistance. In addition, leukemic cells manipulate surrounding BMAds by promoting lipolysis and release of free fatty acids, which are then utilized by leukemic cells via β-oxidation. Therefore, limiting BM adipogenesis, blocking BMAd-derived adipokines, or lipid metabolism obstruction have been considered as potential treatment options for hematological malignancies. Leukemic stem cells rely heavily on BMAds within the structural BM microenvironment for necessary signals which foster disease progression. Further development of 3D constructs resembling BMAT at different skeletal regions are critical to better understand these relationships in geometric space and may provide essential insight into the development of hematologic malignancies within the BM niche. In turn, these mechanisms provide promising potential as novel approaches to targeting the microenvironment with new therapeutic strategies.

High circulating concentrations of estradiol are anabolic for bone mass and strength in an adult male to female transgender mouse model

The effects of gender affirming hormone therapy (GAHT) on bone microarchitecture and fracture risk in adult transgender women is unclear. To investigate the concept that skeletal integrity and strength in trans women may be improved by treatment with a higher dose of GAHT than commonly prescribed, we treated adult male mice with a sustained, high dose of estradiol. Adult male mice at 16 weeks of age were administered ~1.3 mg estradiol by silastic implant, implanted intraperitoneally, for 12 weeks. Controls included vehicle treated intact females and males. High-dose estradiol treatment in males stimulated the endocortical deposition of bone at the femoral mid-diaphysis, increasing cortical thickness and bone area. This led to higher stiffness, maximum force, and the work required to fracture the bone compared to male controls, while post-yield displacement was unaffected. Assessment of the material properties of the bone showed an increase in both elastic modulus and ultimate stress in the estradiol treated males. Treatment of male mice with high dose estradiol was also anabolic for trabecular bone, markedly increasing trabecular bone volume, number and thickness in the distal metaphysis which was accompanied by an increase in the histomorphometric markers of bone remodelling, mineralizing surface/bone surface, bone formation rate and osteoclast number. In conclusion, a high dose of estradiol is anabolic for cortical and trabecular bone in a male to female transgender mouse model, increasing both stiffness and strength. These findings suggest that increasing the current dose of GAHT administered to trans women, while considering other potential adverse effects, may be beneficial to preserving their bone microstructure and strength.

Luminescent Alendronic Acid-Conjugated Micellar Nanostructures for Potential Application in the Bone-Targeted Delivery of Cholecalciferol

Vitamin D, an essential micronutrient crucial for skeletal integrity and various non-skeletal physiological functions, exhibits limited bioavailability and stability in vivo. This study is focused on the development of polyethylene glycol (PEG)-grafted phospholipid micellar nanostructures co-encapsulating vitamin D3 and conjugated with alendronic acid, aimed at active bone targeting. Furthermore, these nanostructures are rendered optically traceable in the UV–visible region of the electromagnetic spectrum via the simultaneous encapsulation of vitamin D3 with carbon dots, a newly emerging class of fluorescents, biocompatible nanoparticles characterized by their resistance to photobleaching and environmental friendliness, which hold promise for future in vitro bioimaging studies. A systematic investigation is conducted to optimize experimental parameters for the preparation of micellar nanostructures with an average hydrodynamic diameter below 200 nm, ensuring colloidal stability in physiological media while preserving the optical luminescent properties of the encapsulated carbon dots. Comprehensive chemical-physical characterization of these micellar nanostructures is performed employing optical and morphological techniques. Furthermore, their binding affinity for the principal inorganic constituent of bone tissue is assessed through a binding assay with hydroxyapatite nanoparticles, indicating significant potential for active bone-targeting. These formulated nanostructures hold promise for novel therapeutic interventions to address skeletal-related complications in cancer affected patients in the future.