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JCI Insight Jun 2024Osteoporotic fractures are a major complication of long-term glucocorticoid therapy. Glucocorticoids transiently increase bone resorption, but they predominantly inhibit...
Osteoporotic fractures are a major complication of long-term glucocorticoid therapy. Glucocorticoids transiently increase bone resorption, but they predominantly inhibit bone formation and induce osteocyte apoptosis, leading to bone loss. Current treatments of glucocorticoid-induced osteoporosis aim mainly at reducing bone resorption and are therefore inadequate. We previously showed that signaling via the NO/cGMP/protein kinase G pathway plays a key role in skeletal homeostasis. Here, we show that pharmacological PKG activation with the guanylyl cyclase-1 activator cinaciguat or expression of a constitutively-active, mutant PKG2R242Q restored proliferation, differentiation, and survival of primary mouse osteoblasts exposed to dexamethasone. Cinaciguat treatment of wild type mice or osteoblast-specific expression of PKG2R242Q in transgenic mice prevented dexamethasone-induced loss of cortical bone mass and strength. These effects of cinaciguat and PKG2R242Q expression were due to preserved bone formation parameters and osteocyte survival. The basis for PKG2's effects appeared to be through recovery of Wnt/β-catenin signaling, which was suppressed by glucocorticoids but is critical for proliferation, differentiation, and survival of osteoblast-lineage cells. Cinaciguat reduced dexamethasone activation of osteoclasts, but this did not occur in the PKG2R242Q transgenic mice, suggesting a minor role in osteoprotection. We propose that existing PKG-targeting drugs could represent a novel therapeutic approach to prevent glucocorticoid-induced osteoporosis.
PubMed: 38885330
DOI: 10.1172/jci.insight.175089 -
Stem Cells Translational Medicine Jun 2024Mechanical force-mediated bone remodeling is crucial for various physiological and pathological processes involving multiple factors, including stem cells and the immune...
Mechanical force-mediated bone remodeling is crucial for various physiological and pathological processes involving multiple factors, including stem cells and the immune response. However, it remains unclear how stem cells respond to mechanical stimuli to modulate the immune microenvironment and subsequent bone remodeling. Here, we found that mechanical force induced increased expression of CD109 on periodontal ligament stem cells (PDLSCs) in vitro and in periodontal tissues from the force-induced tooth movement rat model in vivo, accompanied by activated alveolar bone remodeling. Under mechanical force stimulation, CD109 suppressed the osteogenesis capacity of PDLSCs through the JAK/STAT3 signaling pathway, whereas it promoted PDLSC-induced osteoclast formation and M1 macrophage polarization through paracrine. Moreover, inhibition of CD109 in vivo by lentivirus-shRNA injection increased the osteogenic activity and bone density in periodontal tissues. On the contrary, it led to decreased osteoclast numbers and pro-inflammatory factor secretion in periodontal tissues and reduced tooth movement. Mechanistically, mechanical force-enhanced CD109 expression via the repression of miR-340-5p. Our findings uncover a CD109-mediated mechanical force response machinery on PDLSCs, which contributes to regulating the immune microenvironment and alveolar bone remodeling during tooth movement.
PubMed: 38885217
DOI: 10.1093/stcltm/szae035 -
BioMed Research International 2024Diabetes has a significant global prevalence. Chronic hyperglycemia affects multiple organs and tissues, including bones. A large number of diabetic patients develop... (Review)
Review
Diabetes has a significant global prevalence. Chronic hyperglycemia affects multiple organs and tissues, including bones. A large number of diabetic patients develop osteoporosis; however, the precise relationship between diabetes and osteoporosis remains incompletely elucidated. The activation of the AGE-RAGE signaling pathway hinders the differentiation of osteoblasts and weakens the process of bone formation due to the presence of advanced glycation end products. High glucose environment can induce ferroptosis of osteoblasts and then develop osteoporosis. Hyperglycemia also suppresses the secretion of sex hormones, and the reduction of testosterone is difficult to effectively maintain bone mineral density. As diabetes therapy, thiazolidinediones control blood glucose by activating PPAR-. Activated PPAR- can promote osteoclast differentiation and regulate osteoblast function, triggering osteoporosis. The effects of metformin and insulin on bone are currently controversial. Currently, there are no appropriate tools available for assessing the risk of fractures in diabetic patients, despite the fact that the occurrence of osteoporotic fractures is considerably greater in diabetic individuals compared to those without diabetes. Further improving the inclusion criteria of FRAX risk factors and clarifying the early occurrence of osteoporosis sites unique to diabetic patients may be an effective way to diagnose and treat diabetic osteoporosis and reduce the risk of fracture occurrence.
Topics: Humans; Osteoporosis; Risk Factors; Osteoporotic Fractures; Fractures, Bone; Metabolic Networks and Pathways; Diabetes Mellitus; Bone Density; Osteoblasts; Signal Transduction
PubMed: 38884020
DOI: 10.1155/2024/6640796 -
Frontiers in Endocrinology 2024Postmenopausal osteoporosis is a prevalent disease that affects the bone health of middle-aged and elderly women. The link between gut microbiota and bone health, known...
BACKGROUND
Postmenopausal osteoporosis is a prevalent disease that affects the bone health of middle-aged and elderly women. The link between gut microbiota and bone health, known as the gut-bone axis, has garnered widespread attention.
METHODS
We employed a two-sample Mendelian randomization approach to assess the associations between gut microbiota with osteoclasts and postmenopausal osteoporosis, respectively. Single nucleotide polymorphisms associated with the composition of gut microbiota were used as instrumental variables. By analyzing large-scale multi-ethnic GWAS data from the international MiBioGen consortium, and combining data from the eQTLGen consortium and the GEFOS consortium, we identified microbiota related to osteoclasts and postmenopausal osteoporosis. Key genes were further identified through MAGMA analysis, and validation was performed using single-cell data GSE147287.
RESULTS
The outcomes of this study have uncovered significant associations within the gut microbiome community, particularly with the Burkholderiales order, which correlates with both an increase in osteoclasts and a reduced risk of postmenopausal osteoporosis. with an odds ratio (OR) of 0.400, and a P-value of 0.011. Further analysis using single-cell data allowed us to identify two key genes, FMNL2 and SRBD1, that are closely linked to both osteoclasts and osteoporosis.
CONCLUSION
This study utilizing Mendelian randomization and single-cell data analysis, provides new evidence of a causal relationship between gut microbiota and osteoclasts, as well as postmenopausal osteoporosis. It was discovered that the specific microbial group, the Burkholderiales order, significantly impacts both osteoporosis and osteoclasts. Additionally, key genes FMNL2 and SRBD1 were identified, offering new therapeutic strategies for the treatment of postmenopausal osteoporosis.
Topics: Humans; Mendelian Randomization Analysis; Osteoporosis, Postmenopausal; Female; Osteoclasts; Gastrointestinal Microbiome; Polymorphism, Single Nucleotide; Genome-Wide Association Study; Middle Aged; Bone and Bones; Aged
PubMed: 38883609
DOI: 10.3389/fendo.2024.1419566 -
Journal of Pharmacy & Bioallied Sciences Apr 2024Inflammatory chemicals are released by the immune system in response to any perceived danger, including irritants and pathogenic organisms. The caspase activation and... (Review)
Review
Inflammatory chemicals are released by the immune system in response to any perceived danger, including irritants and pathogenic organisms. The caspase activation and the response of inflammation are governed by inflammasomes, which are sensors and transmitters of the innate immune system. They have always been linked to swelling and pain. Research has mainly concentrated on the NOD-like protein transmitter 3 (NLRP3) inflammasome. Interleukin (IL)-1 and IL-18 are pro-inflammatory cytokines that are activated by the NOD-like antibody protein receptor 3 (NLRP3), which controls innate immune responses. The NLRP3 inflammasome has been associated with gum disease and other autoimmune inflammatory diseases in several studies. Scientists' discovery of IL-1's central role in the pathophysiology of numerous autoimmune disorders has increased public awareness of these conditions. The first disease to be connected with aberrant inflammasome activation was the autoinflammatory cryopyrin-associated periodic syndrome (CAPS). Targeted therapeutics against IL-1 have been delayed in development because their underlying reasons are poorly understood. The NLRP3 inflammasome has recently been related to higher production and activation in periodontitis. Multiple periodontal cell types are controlled by the NLRP3 inflammasome. To promote osteoclast genesis, the NLRP3 inflammasome either increases receptor-activator of nuclear factor kappa beta ligand (RANKL) synthesis or decreases osteoclast-promoting gene (OPG) levels. By boosting cytokines that promote inflammation in the periodontal ligament fibroblasts and triggering apoptosis in osteoblasts, the NLRP3 inflammasome regulates immune cell activity. These findings support further investigation into the NLRP3 inflammasome as a therapeutic target for the medical treatment of periodontitis. This article provides a short overview of the NLRP3 inflammatory proteins and discusses their role in the onset of autoinflammatory disorders (AIDs) and periodontitis.
PubMed: 38882867
DOI: 10.4103/jpbs.jpbs_1118_23 -
Gallium-containing mesoporous nanoparticles influence in-vitro osteogenic and osteoclastic activity.Biomaterials Advances Jun 2024Mesoporous silica nanoparticles were synthesized using a microemulsion-assisted sol-gel method, and calcium, gallium or a combination of both, were used as dopants. The...
Mesoporous silica nanoparticles were synthesized using a microemulsion-assisted sol-gel method, and calcium, gallium or a combination of both, were used as dopants. The influence of these metallic ions on the physicochemical properties of the nanoparticles was investigated by scanning and transmission electron microscopy, as well as N adsorption-desorption methods. The presence of calcium had a significant impact on the morphology and textural features of the nanoparticles. The addition of calcium increased the average diameter of the nanoparticles from 80 nm to 150 nm, while decreasing their specific surface area from 972 m/g to 344 m/g. The nanoparticles of all compositions were spheroidal, with a disordered mesoporous structure. An ion release study in cell culture medium demonstrated that gallium was released from the nanoparticles in a sustained manner. In direct contact with concentrations of up to 100 μg/mL of the nanoparticles, gallium-containing nanoparticles did not exhibit cytotoxicity towards pre-osteoblast MC3T3-E1 cells. Moreover, in vitro cell culture tests revealed that the addition of gallium to the nanoparticles enhanced osteogenic activity. Simultaneously, the nanoparticles disrupted the osteoclast differentiation of RAW 264.7 macrophage cells. These findings suggest that gallium-containing nanoparticles possess favorable physicochemical properties and biological characteristics, making them promising candidates for applications in bone tissue regeneration, particularly for unphysiological or pathological conditions such as osteoporosis.
PubMed: 38878645
DOI: 10.1016/j.bioadv.2024.213922 -
Nature Communications Jun 2024Interactions between osteolineage cells and myeloid cells play important roles in maintaining skeletal homeostasis. Herein, we find that osteolineage cells transfer...
Interactions between osteolineage cells and myeloid cells play important roles in maintaining skeletal homeostasis. Herein, we find that osteolineage cells transfer mitochondria to myeloid cells. Impairment of the transfer of mitochondria by deleting MIRO1 in osteolineage cells leads to increased myeloid cell commitment toward osteoclastic lineage cells and promotes bone resorption. In detail, impaired mitochondrial transfer from osteolineage cells alters glutathione metabolism and protects osteoclastic lineage cells from ferroptosis, thus promoting osteoclast activities. Furthermore, mitochondrial transfer from osteolineage cells to myeloid cells is involved in the regulation of glucocorticoid-induced osteoporosis, and glutathione depletion alleviates the progression of glucocorticoid-induced osteoporosis. These findings reveal an unappreciated mechanism underlying the interaction between osteolineage cells and myeloid cells to regulate skeletal metabolic homeostasis and provide insights into glucocorticoid-induced osteoporosis progression.
Topics: Animals; Mitochondria; Bone Resorption; Osteoclasts; Myeloid Cells; Osteoporosis; Mice; Ferroptosis; Glucocorticoids; Glutathione; Mice, Inbred C57BL; Cell Differentiation; Mice, Knockout; Humans; Male
PubMed: 38877020
DOI: 10.1038/s41467-024-49159-3 -
Frontiers in Pharmacology 2024Natural polyphenols may have a role in counteracting oxidative stress, which is associated with aging and several bone-related diseases. Chlorogenic acid (CGA) is a... (Review)
Review
Natural polyphenols may have a role in counteracting oxidative stress, which is associated with aging and several bone-related diseases. Chlorogenic acid (CGA) is a naturally occurring polyphenolic compound formed by the esterification of caffeic and quininic acids with osteogenic, antioxidant, and anti-inflammatory properties. This review discusses the potential of CGA to enhance osteogenesis by increasing the osteogenic capacity of mesenchymal stem cells (MSCs), osteoblast survival, proliferation, differentiation, and mineralization, as well as its ability to attenuate osteoclastogenesis by enhancing osteoclast apoptosis and impeding osteoclast regeneration. CGA can be involved in bone remodeling by acting directly on pro-osteoclasts/osteoblasts or indirectly on osteoclasts by activating the nuclear factor kB (RANK)/RANK ligand (RANKL)/acting osteoprotegerin (OPG) system. Finally, we provide perspectives for using CGA to treat bone diseases.
PubMed: 38873428
DOI: 10.3389/fphar.2024.1396354 -
Frontiers in Endocrinology 2024Liraglutide (Lrg), a novel anti-diabetic drug that mimics the endogenous glucagon-like peptide-1 to potentiate insulin secretion, is observed to be capable of partially... (Review)
Review
INTRODUCTION
Liraglutide (Lrg), a novel anti-diabetic drug that mimics the endogenous glucagon-like peptide-1 to potentiate insulin secretion, is observed to be capable of partially reversing osteopenia. The aim of the present study is to further investigate the efficacy and potential anti-osteoporosis mechanisms of Lrg for improving bone pathology, bone- related parameters under imageology, and serum bone metabolism indexes in an animal model of osteoporosis with or without diabetes.
METHODS
Eight databases were searched from their inception dates to April 27, 2024. The risk of bias and data on outcome measures were analyzed by the CAMARADES 10-item checklist and Rev-Man 5.3 software separately.
RESULTS
Seventeen eligible studies were ultimately included in this review. The number of criteria met in each study varied from 4/10 to 8/10 with an average of 5.47. The aspects of blinded induction of the model, blinding assessment of outcome and sample size calculation need to be strengthened with emphasis. The pre-clinical evidence reveals that Lrg is capable of partially improving bone related parameters under imageology, bone pathology, and bone maximum load, increasing serum osteocalcin, N-terminal propeptide of type I procollagen, and reducing serum c-terminal cross-linked telopeptide of type I collagen (P<0.05). Lrg reverses osteopenia likely by activating osteoblast proliferation through promoting the Wnt signal pathway, p-AMPK/PGC1α signal pathway, and inhibiting the activation of osteoclasts by inhibiting the OPG/RANKL/RANK signal pathway through anti-inflammatory, antioxidant and anti-autophagic pathways. Furthermore, the present study recommends that more reasonable usage methods of streptozotocin, including dosage and injection methods, as well as other types of osteoporosis models, be attempted in future studies.
DISCUSSION
Based on the results, this finding may help to improve the priority of Lrg in the treatment of diabetes patients with osteoporosis.
Topics: Liraglutide; Animals; Osteoporosis; Disease Models, Animal; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Diabetes Mellitus, Experimental; Bone Density
PubMed: 38868747
DOI: 10.3389/fendo.2024.1378291 -
Journal of Orthopaedic Translation May 2024Age-related mandibular osteoporosis frequently causes loose teeth, difficulty eating, and disfiguration in elders. Bmi1 mice displaying accelerated skeletal aging...
BACKGROUND
Age-related mandibular osteoporosis frequently causes loose teeth, difficulty eating, and disfiguration in elders. Bmi1 mice displaying accelerated skeletal aging represent a useful model for testing interventions against premature jaw bone loss. As an anti-aging agent, metformin may ameliorate molecular dysfunction driving osteoporosis pathogenesis. We explored the mechanisms of mandibular osteopenia in Bmi1 mice and prevention by metformin treatment.
METHODS
Three mouse groups were utilized: wild-type controls, untreated Bmi1, and Bmi1 receiving 1 g/kg metformin diet. Mandibular bone phenotype was assessed by X-ray, micro-CT, histology, and immunohistochemistry. AMPK-mTOR pathway analysis, senescence markers, osteoblast and osteoclast gene expression were evaluated in jaw tissue. Osteoclast differentiation capacity and associated signaling molecules were examined in cultured Bmi1 bone marrow mononuclear cells ± metformin.
RESULTS
Bmi1 loss reduced mandible bone density concomitant with decreased AMPK activity, increased mTOR signaling and cellular senescence in jaw tissue versus wild-type controls. This was accompanied by impaired osteoblast function and upregulated osteoclastogenesis markers. Metformin administration normalized AMPK-mTOR balance, oxidative stress and senescence signaling to significantly improve mandibular bone architecture in Bmi1 mice. In culture, metformin attenuated excessive osteoclast differentiation from Bmi1 marrow precursors by correcting dysregulated AMPK-mTOR-p53 pathway activity and suppressing novel pro-osteoclastogenic factor Stfa1.
CONCLUSIONS
Our study newly demonstrates metformin prevents accelerated jaw bone loss in a premature aging murine model by rectifying molecular dysfunction in cellular energy sensors, redox state, senescence and osteoclastogenesis pathways. Targeting such age-associated mechanisms contributing to osteoporosis pathogenesis may help maintain oral health and aesthetics in the growing elderly population.
TRANSLATIONAL POTENTIAL
The pronounced mandibular osteopenia exhibited in Bmi1 mice represents an accelerated model of jaw bone deterioration observed during human aging. Our finding that metformin preserves mandibular bone integrity in this progeroid model has important clinical implications. As an inexpensive oral medication already widely used to manage diabetes, metformin holds translational promise for mitigating age-related osteoporosis. The mandible is essential for chewing, swallowing, speech and facial structure, but progressively loses bone mass and strength with advancing age, significantly impacting seniors' nutrition, physical function and self-image. Our results suggest metformin's ability to rectify cellular energy imbalance, oxidative stress and osteoclast overactivity may help maintain jaw bone health into old age. Further research is still needed given metformin's multifaceted biology and bone regulation by diverse pathways. However, this preclinical study provides a strong rationale for clinical trials specifically examining mandibular outcomes in elderly subjects receiving standard metformin treatment for diabetes or prediabetes. Determining if metformin supplementation can prevent or delay oral disability and disfigurement from senescent jaw bone loss in the growing aged population represents an important public health priority. In summary, our mechanistic findings in a genetic mouse model indicate metformin merits investigation in rigorous human studies for alleviating morbidity associated with age-related mandibular osteoporosis.
PubMed: 38867742
DOI: 10.1016/j.jot.2024.03.001