Regulation Of Bone Homeostasis Research Articles

The microbial metabolite imidazole propionate dysregulates bone homeostasis by inhibiting AMP-activated protein kinase (AMPK) signaling

Microbial metabolites provide numerous benefits to the human body but can also contribute to diseases such as obesity, diabetes, cancer, and bone disorders. However, the role of imidazole propionate (ImP), a histidine-derived metabolite produced by the intestinal microbiome, in bone metabolism and the development of osteoporosis is still poorly understood. In this study, we investigated the role of ImP and its underlying mechanisms in regulating bone homeostasis. When ImP was administered to 8-week-old mice for 4 weeks, bone loss was observed, along with a decrease in alkaline phosphatase-positive osteoblast cells. Additionally, bone marrow stromal cells (BMSCs) isolated from ImP-treated mice exhibited reduced osteogenic potential. In BMSCs from control mice, ImP treatment inhibited BMP2-induced osteoblast differentiation while promoting adipocyte differentiation. However, ImP had no effect on RANKL-induced osteoclast differentiation or activity in bone marrow macrophages. Mechanistically, ImP treatment increased p38γ phosphorylation and decreased AMPK (T172) phosphorylation in BMSCs. Suppression of p38γ expression using si-p38γ reversed the inhibitory effects of ImP on osteoblast differentiation, with a concurrent increase in AMPK (T172) phosphorylation. Conversely, ImP stimulated adipocyte differentiation by decreasing AMPK (T172) phosphorylation. Treatment with the AMPK agonist metformin significantly reversed the inhibitory effects of ImP on osteoblast differentiation and the promotion of adipocyte differentiation, along with enhanced AMPK (T172) phosphorylation. These findings suggest that the microbial metabolite ImP may disrupt bone homeostasis by stimulating p38γ phosphorylation and inhibiting the AMPK pathway, presenting a potential therapeutic target for managing metabolic bone diseases.

REV-ERBα Inhibits Osteoclastogenesis and Protects against Alveolar Bone Loss.

Circadian rhythm disruption is thought to be associated with periodontitis, and molecular clock genes play critical roles in regulating bone homeostasis. However, the specific contribution of molecular clock genes to alveolar bone resorption caused by periodontitis is poorly understood. In this study, we introduced a novel Periodontitis Circadian Rhythm Score (PeriCRS) model that was established through machine learning using periodontal transcriptomic data from periodontitis clinical cohorts in the Gene Expression Omnibus (GEO) database. This approach revealed the potential regulatory role of circadian rhythm disruption in periodontitis and identified key molecular clock genes associated with alveolar bone destruction. Moreover, we established an experimental periodontitis model with circadian rhythm disturbance via periodontal ligation in mice exposed to a 6-h advanced LD12:12 cycle every 2 d. Our bioinformatics analysis revealed that NR1D1, which encodes REV-ERBα, is a pivotal factor in the impact of circadian rhythm disruption on periodontitis in periodontal tissues. Next, we confirmed the abnormal expression of the molecular clock gene Rev-erbα in inflammatory periodontal tissue in mice and confirmed that circadian rhythm disruption altered REV-ERBα expression. Furthermore, the activation of REV-ERBα with the agonist SR9009 notably decreased RANKL-induced osteoclast differentiation and suppressed the expression of osteoclast-related factors. Subsequent in vivo experiments demonstrated that SR9009 mitigated alveolar bone loss caused by periodontitis. Mechanistically, we found that the IL-22-STAT3 pathway inhibited REV-ERBα expression and modulated RANKL-induced osteoclast differentiation in vitro. Our results elucidate the role of REV-ERBα in osteoclastogenesis and suggest a potential new therapeutic avenue for addressing alveolar bone resorption associated with periodontitis.

Oyster Mantle-Derived Exosomes Alleviate Osteoporosis by Regulating Bone Homeostasis

Osteoporosis is a major public health problem with an urgent need for safe and effective therapeutic interventions. The process of shell formation in oysters is similar to that of bone formation in mammals, and oyster extracts have been proven to exert osteoprotective effects. Oyster mantle is the most crucial organ regulating shell formation, in which exosomes play an important role. However, the effects of oyster mantle-derived exosomes (OMEs) on mammalian osteoporosis and the underlying mechanisms remain unknown. The OMEs investigated herein was found to carry abundant osteogenic cargos. They could also survive hostile gastrointestinal conditions and accumulate in the bones following oral administration. Moreover, they promoted osteoblastic differentiation and inhibited osteoclastic differentiation simultaneously. Further mechanistic examination revealed that OMEs likely promoted osteogenic activity by activating PI3K/Akt/β-catenin pathway in osteoblasts and blunted osteoclastic activity by inhibiting NF-κB pathway in osteoclasts. These favorable pro-osteogenic effects of OMEs were also corroborated in a rat femur defect model. Importantly, oral administration of OMEs effectively attenuated bone loss and improved the bone microstructure in ovariectomy-induced osteoporotic mice, and demonstrating excellent biosafety. The mechanistic insights from our data support that OMEs possess promising therapeutic potential against osteoporosis.

Inhibition of sympathetic tone via hypothalamic descending pathway propagates glucocorticoid-induced endothelial impairment and osteonecrosis of the femoral head

Osteonecrosis of the femoral head (ONFH) is a common complication of glucocorticoid (GC) therapy. Recent advances demonstrate that sympathetic nerves regulate bone homeostasis, and GCs lower the sympathetic tone. Here, we show that the dramatically decreased sympathetic tone is closely associated with the pathogenesis of GC-induced ONFH. GCs activate the glucocorticoid receptor (GR) but hinder the activation of the mineralocorticoid receptor (MR) on neurons in the hypothalamic paraventricular nucleus (PVN). This disrupts the balance of corticosteroid receptors (GR/MR) and subsequently reduces the sympathetic outflow in the PVN. Vascular endothelial cells rapidly react to inhibition of sympathetic tone by provoking endothelial apoptosis in adult male mice treated with methylprednisolone (MPS) daily for 3 days, and we find substantially reduced H-type vessels in the femoral heads of MPS-treated ONFH mice. Importantly, treatment with a GR inhibitor (RU486) in the PVN promotes the activation of MR and rebalances the ratio of GR and MR, thus effectively boosting sympathetic outflow, as shown by an increase in tyrosine hydroxylase expression in both the PVN and the sympathetic postganglionic neurons and an increase in norepinephrine levels in both the serum and bone marrow of the femoral head of MPS-treated mice. Rebalancing the corticosteroid receptors mitigates GC-induced endothelial impairment and ONFH and promotes angiogenesis coupled with osteogenesis in the femoral head, while these effects are abolished by chemical sympathectomy with 6-OHDA or adrenergic receptor-β2 (Adrb2) knockout. Furthermore, activating Adrb2 signaling in vivo is sufficient to rescue the GC-induced ONFH phenotype. Mechanistically, norepinephrine increases the expression of the key glycolytic gene 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) via Adrb2-cyclic AMP response element-binding protein (CREB) signaling. Endothelial-specific overexpression of PFKFB3 attenuates endothelial impairment and prevents severe osteonecrosis in MPS-treated Adrb2 knockout mice. Thus, GC inhibits sympathetic tone via the hypothalamic descending pathway, which, in turn, acts as a mediator of GC-induced ONFH.

Damascenone inhibits osteoclastogenesis by epigenetically modulating Nrf2-mediated ROS scavenge and counteracts OVX-induced osteoporosis

BackgroundBone formation and resorption regulate bone homeostasis. Excessive osteoclastogenesis enhances bone resorption and causes osteoporosis. Although medicines targeting osteoclast have been developed, these drugs have several side effects. Natural compounds have advantages in safety and efficiency, making them potential candidates for osteoporosis treatment. PurposeThis study aims to elucidate the role of damascenone (Dama) in osteoclastogenesis and osteoporosis. Study design and methodsTo demonstrate the effect of Dama on osteoclast differentiation and function, we performed multiple in vitro experiments including TRAP staining, F-actin staining, bone slice resorption assay, real-time PCR, and western bolt. Further, ROS detection, network pharmacology, microscale thermophoresis assay, and ChIP assay were conducted to elucidate the underlying molecular mechanism. Finally, the in vivo effects of Dama were verified using an ovariectomy induced osteoporosis mice model. ResultsDama inhibited RANKL-induced osteoclast differentiation and bone resorptive function in vitro. The expression of osteoclast-related genes and activation of MAPKs and NF-κB signaling in osteoclast were also attenuated by Dama. Meanwhile, Dama reduced intracellular ROS level via up-regulating Nrf2 expression. Network pharmacology demonstrated that HDAC2 is the potential direct target of Dama. Dama inhibited HDAC2 function and increased H3K27ac level of Nrf2, which induced Nrf2 expression and activated ROS scavenging enzymes. Inhibiting NRF2 or activating HDAC2 attenuated the effect of Dama on osteoclastogenesis. Finally, Dama injection suppressed in vivo osteoclastogenesis and ameliorated bone loss induced by OVX. ConclusionDama attenuates osteoclastogenesis by epigenetically modulating Nrf2 expression and ROS scavenge. This study provides evidence for Dama being a potential treatment for osteoporosis.

Bioinspired Glycopeptide Hydrogel Reestablishing Bone Homeostasis through Mediating Osteoclasts and Osteogenesis in Periodontitis Treatment.

Irreversible alveolar bone resorption is one of the important clinical manifestations of periodontitis, which is initiated by a plaque biofilm and exacerbated by the imbalance of osteoclast activity and osteogenesis, affecting a patient's masticatory function and resulting in a high recurrence rate of periodontitis. Herein, to reestablish bone homeostasis in periodontitis, a minocycline hydrochloride (MH)-loaded glycopeptide hydrogel (MH/GRWgel) is fabricated to mediate alveolar bone absorption through sequential antibacterial and RANKL-blocking activities. GRWgel shows an ECM-like fibrous and porous microstructure serving as a scaffold for cell proliferation and differentiation and holds the merits including injectability, self-healing properties, and good biocompatibility. After injection in situ, MH is released rapidly from the hydrogel in the early stage, demonstrating a potent antimicrobial effect to combat the biofilm in the deep periodontal pocket. Moreover, MH/GRWgel exhibits a high specific binding efficiency with RANKL to suppress osteoclast maturation by shielding the RANKL/RANK interaction and enhancing osteogenic differentiation, thereby synergistically regulating bone homeostasis. In the rat periodontitis model, MH/GRWgel significantly curtails periodontitis progression through antimicrobial activity, inhibition of alveolar bone resorption, and promotion of bone regeneration, which is superior to the treatment of a commercial gel. These findings suggest that MH/GRWgel with superiority in regulating bone homeostasis provides a promising therapeutic strategy for periodontitis.

Low-intensity pulsed ultrasound regulates bone marrow mesenchymal stromal cells differentiation and inhibits bone loss by activating the IL-11-Wnt/β-catenin signaling pathway

BackgroundOsteoporosis (OP) is a common metabolic bone disease. Low-intensity pulsed ultrasound (LIPUS) can effectively promote bone formation and fracture healing. The Wnt/β-catenin signaling pathway is crucial for regulating bone homeostasis and bone diseases, and its downregulation is one of the main mechanisms of osteoporosis pathogenesis. Interleukin-11 (IL-11), which is regulated by mechanical stress, is a key factor in bone remodeling. Here, we investigated the optimal intervention parameters for LIPUS, the relationships among LIPUS, IL-11, and the Wnt/β-catenin signaling pathway, and the effects of LIPUS on bone loss and potential molecular mechanisms in ovariectomized (OVX) mice. MethodsBone marrow mesenchymal stromal cells (BMSCs) were subjected to LIPUS intervention for 0, 10, or 20 min to determine the optimal intervention time. The mediating role of IL-11 in LIPUS intervention was explored through IL-11 knockdown and overexpression. Finally, animal experiments were conducted to investigate the in vivo therapeutic effects of LIPUS. ResultsThe optimal intervention time for LIPUS was 20 min. LIPUS promoted IL-11 expression and upregulated the Wnt/β-catenin signaling pathway, thereby promoting osteogenic differentiation and inhibiting adipogenic differentiation of BMSCs. IL-11 mediates the regulation of the Wnt/β-catenin signaling pathway by LIPUS. Additionally, LIPUS effectively improved the bone microstructure in ovariectomized mice, inhibited bone loss, promoted IL-11 expression in bone tissue, and activated the Wnt/β-catenin signaling pathway in the femur. ConclusionLow-intensity pulsed ultrasound can regulate BMSCs differentiation and inhibit bone loss by promoting IL-11 expression and activating the Wnt/β-catenin signaling pathway.

Irg1 regulates bone homeostasis via regulating the Grk5 expression

We have previously demonstrated that itaconic acid can regulate osteoclast differentiation in vitro and in vivo, thereby affecting the progression of osteoporosis. The role of Irg1 as itaconic acid catalytic enzyme in bone homeostasis has not been clearly elucidated. Here, we detected enhanced the osteoclast differentiation in Irg1-deficiency BMMs, along with the expression of genes associated with osteoclastogenesis. Irg1 knockout promoted the expression of Nfatc1 and F-actin ring formation, with the inhibited production of itaconate. RNA-seq analysis was carried out and we proved that Grk5 expression was increased the most. Inhibition of Grk5 attenuated the effect of Irg1 in the osteoclastogenesis. However, micro-CT analysis showed no significant difference of bone trabecular structure in Irg1 knockout mice. Moreover, we observed no significant difference of osteoclasts numbers in the femur of Irg1 knockout mice in vivo. And similar bone formation was detected between the Irg1 knockout and WT mice, indicating that irg1 had slight effect on the bone homeostasis under physiological conditions. Surprising, we detected higher level of inflammatory factors in the bone tissues of Irg1 knockout mice. Above all, we for the first time demonstrated that Irg1 knockout promoted the osteoclastogenesis via regulating the Grk5 signaling. Regulation of irg1-Grk5 axis could be effective in treating human diseases under pathological situations in the future.

Research progress on the regulatory cell death of osteoblasts in periodontitis

Periodontitis is a chronic inflammatory disease characterized by progressive destruction of alveolar bone. The most critical mechanism underlying alveolar bone destruction is the imbalance of bone homeostasis, where osteoblast-mediated bone matrix synthesis plays an important role in regulating bone homeostasis. Regulated cell death is instrumental in both the inflammatory microenvironment and the regulation of bone homeostasis. Chronic inflammation, oxidative stress, and other factors can be directly involved in mitochondrial and death receptor-mediated signaling pathways, modulating B-cell lymphoma 2 family proteins and cysteine aspartic acid specific protease (caspase) activity, thereby affecting osteoblast apoptosis and alveolar bone homeostasis. Chronic inflammation and cellular damage induce osteoblast necroptosis via the RIPK1/RIPK3/MLKL signaling pathway, exacerbating the inflammatory response and accelerating alveolar bone destruction. Stimuli such as pathogenic microorganisms and cellular injury may also activate caspase-1-dependent or independent signaling pathways and gasdermin D family proteins, promoting osteoblast pyroptosis and releasing pro-inflammatory cytokines to mediate alveolar bone damage. Iron overload and lipid peroxidation in periodontitis can trigger ferroptosis in osteoblasts, impacting their survival and function, ultimately leading to bone homeostasis imbalance. This article focuses on the mechanism of periodontal disease affecting bone homeostasis through regulatory cell death, aiming to provide research evidence for the treatment of periodontitis and alveolar bone homeostasis imbalance.

Herbal medicine Ninjinyoeito inhibits RANKL-induced osteoclast differentiation and bone resorption activity by regulating NF-κB and MAPK pathway

ObjectivesOsteoporosis is a systemic bone metabolism disorder characterized by decreased bone mass and strength. Osteoclasts (OCs) are giant multinucleated cells that regulate bone homeostasis by degrading bone matrix. Excessive OC differentiation and activity can lead to serious bone metabolic disorders including osteoporosis. Current treatments, including antiresorptive drugs, exert considerable adverse effects, including jaw osteonecrosis. Herbal medicines, such as Ninjinyoeito (NYT), may also offer efficacy, but with fewer adverse effects. In this study, we investigated NYT's effects on osteoclastogenesis. MethodsTartrate-resistant acid phosphatase (TRAP) staining and bone resorption assays were performed to examine NYT's effects on OC differentiation and function. OC-related gene expression at mRNA and protein levels was investigated to confirm NYT's inhibitory action against osteoclastogenesis. We also demonstrated involvement of signaling pathways mediated by IκBα and mitogen-activated protein kinases (MAPK) [extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38] and showed nuclear translocation of nuclear factor of activated T-cell cytoplasmic 1 (NFATc1) and nuclear factor kappa B (NF-κB) p65 during osteoclastogenesis. ResultsTRAP staining and bone resorption assays confirmed that NYT significantly inhibited OC differentiation and function. Western blot and RT-PCR results showed that NYT ameliorated osteoclastogenesis by suppressing mRNA and protein level expression of OC-related genes. Moreover, blots and immunocytochemistry (ICC) data clarified that NYT abrogates signaling pathways mediated by IκBα and MAPK (ERK, JNK, p38), and demonstrated nuclear translocation of NFATc1 and NF-κB p65 during OC differentiation. ConclusionsThese findings suggest NYT is an alternative therapeutic candidate for treating osteoporosis.

Antioxidant enzyme Prdx1 inhibits osteoclastogenesis via suppressing ROS and NFATc1 signaling pathways.

Bone is a dynamic organ which continuously undergoes remodeling throughout one's lifetime. Cellular production of reactive oxygen species (ROS) is essential for regulating bone homeostasis. Osteoclasts, multinucleated giant cells differentiated from macrophage lineage, are responsible for osteolytic bone conditions which are closely linked to ROS signaling pathways. In this study, an anti-ROS enzyme, peroxiredoxin 1 (Prdx1) was found to be expressed both in bone marrow macrophages and osteoclasts. Recombinant Prdx1 protein was found to dose-dependently inhibit ROS production and osteoclast differentiation. Mechanistically, Prdx1 protein also attenuated NFATc1 activation as well as the expression of C-Fos, V-ATPase-d2, Cathepsin K, and Integrin αV. Collectively, Prdx1 is a negative regulator on osteoclast formation via inhibiting RANKL-mediated ROS activity, thus suggesting its potential application for treating osteoclast related disorders.

USP10-mediated deubiquitination of NR3C1 regulates bone homeostasis by controlling CST3 expression

Dysregulated bone homeostasis contributes to multiple diseases including osteoporosis (OP). In this study, osteoporotic mice were successfully generated using ovariectomy to investigate the role of nuclear receptor subfamily 3 group C member 1 (NR3C1) in OP. NR3C1, identified as a significantly upregulated gene in OP using bioinformatic tools, was artificially downregulated in osteoporotic mice. NR3C1 expression was significantly elevated in the femoral tissues of osteoporotic patients, and downregulation of NR3C1 alleviated bone loss and restored bone homeostasis in osteoporotic mice, as manifested by increased ALP- and OCN-positive cells and reduced RANKL/OPG ratio. Downregulation of NR3C1 inhibited osteoclastic differentiation of RAW264.7 cells and mouse bone marrow-derived macrophages (BMDM) and promoted osteogenic differentiation of MC3T3-E1 cells. The transcription factor NR3C1 bound to the cystatin-3 (CST3) promoter to repress its transcription in both RAW264.7 and MC3T3-E1 cells. The downregulation of CST3 reversed the protective effect of NR3C1 downregulation against OP. Ubiquitin-specific-processing protease 10 (USP10)-mediated deubiquitination of NR3C1 improved NR3C1 stability. Downregulation of USP10 inhibited osteoclastic differentiation of RAW264.7 cells and BMDM while promoting osteogenic differentiation of MC3T3-E1 cells. Taken together, USP10-mediated deubiquitination of NR3C1 regulates bone homeostasis by controlling CST3 transcription, providing an attractive therapeutic strategy to alleviate OP.

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.

Regulation of bone homeostasis: signaling pathways and therapeutic targets.

As a highly dynamic tissue, bone is continuously rebuilt throughout life. Both bone formation by osteoblasts and bone resorption by osteoclasts constitute bone reconstruction homeostasis. The equilibrium of bone homeostasis is governed by many complicated signaling pathways that weave together to form an intricate network. These pathways coordinate the meticulous processes of bone formation and resorption, ensuring the structural integrity and dynamic vitality of the skeletal system. Dysregulation of the bone homeostatic regulatory signaling network contributes to the development and progression of many skeletal diseases. Significantly, imbalanced bone homeostasis further disrupts the signaling network and triggers a cascade reaction that exacerbates disease progression and engenders a deleterious cycle. Here, we summarize the influence of signaling pathways on bone homeostasis, elucidating the interplay and crosstalk among them. Additionally, we review the mechanisms underpinning bone homeostatic imbalances across diverse disease landscapes, highlighting current and prospective therapeutic targets and clinical drugs. We hope that this review will contribute to a holistic understanding of the signaling pathways and molecular mechanisms sustaining bone homeostasis, which are promising to contribute to further research on bone homeostasis and shed light on the development of targeted drugs.

Differential but complementary roles of HIF-1α and HIF-2α in the regulation of bone homeostasis

Bone is a highly dynamic tissue undergoing continuous formation and resorption. Here, we investigated differential but complementary roles of hypoxia-inducible factor (HIF)-1α and HIF-2α in regulating bone remodeling. Using RNA-seq analysis, we identified that specific genes involved in regulating osteoblast differentiation were similarly but slightly differently governed by HIF-1α and HIF-2α. We found that increased HIF-1α expression inhibited osteoblast differentiation via inhibiting RUNX2 function by upregulation of Twist2, confirmed using Hif1a conditional knockout (KO) mouse. Ectopic expression of HIF-1α via adenovirus transduction resulted in the increased expression and activity of RANKL, while knockdown of Hif1a expression via siRNA or osteoblast-specific depletion of Hif1a in conditional KO mice had no discernible effect on osteoblast-mediated osteoclast activation. The unexpected outcome was elucidated by the upregulation of HIF-2α upon Hif1a overexpression, providing evidence that Hif2a is a transcriptional target of HIF-1α in regulating RANKL expression, verified through an experiment of HIF-2α knockdown after HIF-1α overexpression. The above results were validated in an ovariectomized- and aging-induced osteoporosis model using Hif1a conditional KO mice. Our findings conclude that HIF-1α plays an important role in regulating bone homeostasis by controlling osteoblast differentiation, and in influencing osteoclast formation through the regulation of RANKL secretion via HIF-2α modulation.

A Novel Piezo1 Agonist Promoting Mesenchymal Stem Cell Proliferation and Osteogenesis to Attenuate Disuse Osteoporosis

Disuse osteoporosis (OP) is a state of bone loss due to lack of mechanical stimuli, probably induced by prolonged bed rest, neurological diseases, as well as microgravity. Currently the precise treatment strategies of disuse OP remain largely unexplored. Piezo1, a mechanosensitive calcium (Ca2+) ion channel, is a key force sensor mediating mechanotransduction and it is demonstrated to regulate bone homeostasis and osteogenesis in response to mechanical forces. Using structure‐based drug design, a novel small‐molecule Piezo1 agonist, MCB‐22‐174, which can effectively activate Piezo1 and initiate Ca2+ influx, is developed and is more potent than the canonical Piezo1 agonist, Yoda1. Moreover, MCB‐22‐174 is found as a safe Piezo1 agonist without any signs of serious toxicity. Mechanistically, Piezo1 activation promotes the proliferation of bone marrow mesenchymal stem cells by activating the Ca2+‐related extracellular signal‐related kinases and calcium–calmodulin (CaM)‐dependent protein kinase II (CaMKII) pathway. Importantly, MCB‐22‐174 could effectively promote osteogenesis and attenuate disuse OP in vivo. Overall, the findings provide a promising therapeutic strategy for disuse OP by chemical activation of Piezo1.

Cold exposure-induced plasma exosomes impair bone mass by inhibiting autophagy

Recently, environmental temperature has been shown to regulate bone homeostasis. However, the mechanisms by which cold exposure affects bone mass remain unclear. In our present study, we observed that exposure to cold temperature (CT) decreased bone mass and quality in mice. Furthermore, a transplant of exosomes derived from the plasma of mice exposed to cold temperature (CT-EXO) can also impair the osteogenic differentiation of BMSCs and decrease bone mass by inhibiting autophagic activity. Rapamycin, a potent inducer of autophagy, can reverse cold exposure or CT-EXO-induced bone loss. Microarray sequencing revealed that cold exposure increases the miR-25-3p level in CT-EXO. Mechanistic studies showed that miR-25-3p can inhibit the osteogenic differentiation and autophagic activity of BMSCs. It is shown that inhibition of exosomes release or downregulation of miR-25-3p level can suppress CT-induced bone loss. This study identifies that CT-EXO mediates CT-induced osteoporotic effects through miR-25-3p by inhibiting autophagy via targeting SATB2, presenting a novel mechanism underlying the effect of cold temperature on bone mass.

Engineered Niobium Carbide MXenzyme-Integrated Self-Adaptive Coatings Inhibiting Periprosthetic Osteolysis by Orchestrating Osteogenesis-Osteoclastogenesis Balance.

Periprosthetic osteolysis induced by the ultrahigh-molecular-weight polyethylene (UHMWPE) wear particles is a major complication associated with the sustained service of artificial joint prostheses and often necessitates revision surgery. Therefore, a smart implant with direct prevention and repair abilities is urgently developed to avoid painful revision surgery. Herein, we fabricate a phosphatidylserine- and polyethylenimine-engineered niobium carbide (Nb2C) MXenzyme-coated micro/nanostructured titanium implant (PPN@MNTi) that inhibits UHMWPE particle-induced periprosthetic osteolysis. The specific mechanism by which PPN@MNTi operates involves the bioresponsive release of nanosheets from the MNTi substrate within an osteolysis microenvironment, initiated by the cleavage of a thioketal-dopamine molecule sensitive to reactive oxygen species (ROS). Subsequently, functionalized Nb2C MXenzyme could target macrophages and escape from lysosomes, effectively scavenging intracellular ROS through its antioxidant nanozyme-mimicking activities. This further achieves the suppression of osteoclastogenesis by inhibiting NF-κB/MAPK and autophagy signaling pathways. Simultaneously, based on the synergistic effect of MXenzyme-integrated coatings and micro/nanostructured topography, the designed implant promotes the osteogenic differentiation of bone mesenchymal stem cells to regulate bone homeostasis, further achieving advanced osseointegration and alleviable periprosthetic osteolysis in vivo. This study provides a precise prevention and repair strategy of periprosthetic osteolysis, offering a paradigm for the development of smart orthopedic implants.

Vasculoendothelial dysfunction and bone health in obese children: A connection with cancers

Obesity in children, a growing global epidemic, is not merely characterized by excessive body fat but also by a cascade of metabolic and functional derangements with significant musculoskeletal consequences. One of the key underpinnings of these detrimental effects is vasculoendothelial dysfunction (VED), a multifaceted pathological process characterized by impaired endothelial cell function. The endothelium, lining the vasculature, plays a pivotal role in regulating vascular tone, inflammation, and coagulation, and its dysfunction in obese children leads to a plethora of downstream complications with profound implications for musculoskeletal and bone health. Diagnosing VED in obese children remains a challenge. Traditional cardiovascular risk factors such as hypertension and dyslipidemia are often detected long after the occurrence of endothelial dysfunction. In the context of bone sarcoma, the interaction between cancer cells and vascular endothelium in the bone microenvironment is critical. The bone is a highly vascularized tissue, and the vascular endothelium plays a role in regulating bone homeostasis. In the presence of cancer cells, altered bone microenvironment provides a milieu favorable to tumor growth and invasion. The relationship between the vascular endothelium and cancer is complex and can vary depending on the type of cancer and its microenvironment. Understanding the interactions between vascular endothelium and bone sarcoma is crucial for developing targeted therapies. New molecular and cellular mechanisms involved in these interactions are awaiting to be uncovered, shedding light on potential therapeutic strategies for cancer treatment. On a relevant note, emerging vasculoendothelial markers hold promise for early detection and intervention. Early identification of VED, through the detection of vasculoendothelial markers, opens doors for timely interventions aimed at preventing its detrimental effects on musculoskeletal and bone health in obese children

Effect of gut hormones on bone metabolism and their possible mechanisms in the treatment of osteoporosis.

Bone is a highly dynamic organ that changes with the daily circadian rhythm. During the day, bone resorption is suppressed due to eating, while it increases at night. This circadian rhythm of the skeleton is regulated by gut hormones. Until now, gut hormones that have been found to affect skeletal homeostasis include glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), glucose-dependent insulinotropic polypeptide (GIP), and peptide YY (PYY), which exerts its effects by binding to its cognate receptors (GLP-1R, GLP-2R, GIPR, and Y1R). Several studies have shown that GLP-1, GLP-2, and GIP all inhibit bone resorption, while GIP also promotes bone formation. Notably, PYY has a strong bone resorption-promoting effect. In addition, gut microbiota (GM) plays an important role in maintaining bone homeostasis. This review outlines the roles of GLP-1, GLP-2, GIP, and PYY in bone metabolism and discusses the roles of gut hormones and the GM in regulating bone homeostasis and their potential mechanisms.