-
Biomedicines Aug 2023Individuals with inflammatory bowel disease (IBD) have an increased risk of bone impairment, which is a process controlled by the RANKL/RANK/OPG system, mostly due to...
UNLABELLED
Individuals with inflammatory bowel disease (IBD) have an increased risk of bone impairment, which is a process controlled by the RANKL/RANK/OPG system, mostly due to chronic inflammation and corticosteroid treatment. Bone morphogenic protein 7 (BMP7) has a complex role in maintaining inflammation and bone remodeling but little is known about its anti-inflammatory potential in chronic colitis. We investigated the effect of systemically administered BMP7 and corticosteroids on the severity of inflammation, macrophage differentiation, and bone regeneration in a chronic IBD model.
METHODS
Chronic colitis was induced in male Sprague Dawley rats via weekly administration of 2,4,6-trinitrobenzenesulfonic acid over 21 days following BMP7 or corticosteroid treatment for five days. The levels of serum and colon tissue inflammatory cytokines, RANKL/OPG system, as well as markers of macrophage polarization, were detected using RT-PCR, ELISA, or immunohistochemistry. Long bone and spine analyses were performed using microcomputed tomography (micro-CT).
RESULTS
The administration of BMP7 reduced the adverse effects of colitis and led to elevated OPG and RANK in the colon with a simultaneous decrease in TNF-α and an increase in IL-10 and TGF-β. Decreased expression of the M2 macrophage marker CD163 was found in the BMP7-treated rats compared with the colitis group, whereas the number of M1 marker iNOS-positive cells did not differ between the groups. As a result of the BMP7 treatment, morphometric parameters of trabecular bone increased, and increased trabecular separation noted in the colitis group did not appear.
CONCLUSIONS
We showed that BMP7 suppressed the inflammatory response in chronic colitis, mainly by shifting the cytokine balance and by triggering alterations in the RANKL/OPG system rather than through a macrophage polarization imbalance. In addition, considering the demonstrated effect of BMP7 on bone morphology and structure, it can be suggested that BMP7 plays a role in the managing of osteoporosis in chronic colitis, and thus, its therapeutic potential in the treatment of IBD should be further evaluated.
PubMed: 37626658
DOI: 10.3390/biomedicines11082161 -
Journal of Neurosurgery Jun 2024Aneurysm wall inflammation is associated with lesion instability in unruptured intracranial aneurysms (UIAs). However, most UIAs remain unruptured during lifelong...
OBJECTIVE
Aneurysm wall inflammation is associated with lesion instability in unruptured intracranial aneurysms (UIAs). However, most UIAs remain unruptured during lifelong follow-ups because of simultaneous protective remodeling against the inflammatory response. The protective effects of osteoprotegerin (OPG) in intracranial and abdominal aortic aneurysms have been suggested using rodent models; however, the role of this protein in UIAs in humans remains unclear. Herein, the authors examined the relationship between OPG expression and aneurysm wall integrity in intraoperatively resected UIAs by using immunohistochemical and immunofluorescence staining.
METHODS
Sixteen UIA wall tissue specimens resected between 2017 and 2022 were analyzed. Aneurysm growth was defined as an enlargement > 1 mm or an obvious morphological change over the course of more than 6 months. Three high-power fields were randomly selected from areas expressing high and low levels of OPG within the same aneurysm. To clarify the role of OPG in the human aneurysm wall, the authors compared averaged values for the following pathological features between the 2 OPG expression groups: aneurysm wall thickness, collagen, macrophages, smooth muscle cells, and transforming growth factor beta 1 (TGF-β1). Immunohistochemical staining within the entire tissue area was also analyzed to determine the relationships between OPG expression and different aneurysm growth patterns. Pathological findings were compared between high and low OPG expression levels using the Wilcoxon signed-rank test.
RESULTS
The heterogeneous expression of OPG was detected in the walls of UIAs. Lesions expressing high OPG levels had thicker aneurysm walls (327 vs 180 μm, p = 0.002) and higher expression levels of TGF-β1 (8.5% vs 5.4%, p = 0.002) than those expressing low OPG levels. The expression of TGF-β1 was colocalized with that of OPG mainly in the tunica media. Furthermore, lesions expressing high OPG levels had larger α-SMA+ areas (25% vs 13%, p = 0.002). Aneurysm growth was observed in 6 of 9 UIAs with available data: whole sac expansion in 4 and secondary aneurysm formation in 2. Among the 6 UIAs with aneurysm growth, OPG expression was relatively higher in the UIAs with an internal elastic lamina than in those without (17% vs 6.9%).
CONCLUSIONS
Aneurysm wall integrity was associated with OPG expression in the aneurysm wall. Collectively, the study results indicated that OPG is associated with protective remodeling, which may contribute to the retention of aneurysm wall structures.
Topics: Humans; Intracranial Aneurysm; Osteoprotegerin; Male; Middle Aged; Female; Aged; Transforming Growth Factor beta1; Vascular Remodeling; Adult
PubMed: 38157535
DOI: 10.3171/2023.10.JNS231410 -
Clinical and Experimental Rheumatology Nov 2023Bone erosion in rheumatoid arthritis (RA) is partly caused by excessive activation of osteoclasts. Osteoclasts can be derived from RA synovium and their differentiation...
OBJECTIVES
Bone erosion in rheumatoid arthritis (RA) is partly caused by excessive activation of osteoclasts. Osteoclasts can be derived from RA synovium and their differentiation can be inhibited by osteoprotegerin (OPG), a decoy receptor of the osteoclastogenesis-promoting cytokine receptor activator of nuclear factor κB ligand (RANKL). Fibroblast-like synoviocytes (FLSs) are the main stromal cells in the synovium that can secret OPG. The OPG secretion of FLSs can be modulated by various cytokines. Interleukin (IL)-13 can alleviate bone erosion in RA mouse models, but the mechanisms remain unclear. Therefore, we aimed to investigate whether IL-13 can induce OPG secretion by RA-FLSs, thus ameliorating bone destruction in RA by inhibiting osteoclast differentiation.
METHODS
OPG, RANKL, and IL-13 receptors expression by RA-FLSs were evaluated by RT-qPCR. OPG secretion was determined by ELISA. Western blot was performed to analyse OPG expression and the activation of the STAT6 pathway. IL-13 and (or) OPG siRNA pre-treated RA-FLSs conditioned medium were used in osteoclast induction to test if IL-13 can inhibit osteoclastogenesis by up-regulating OPG in RA-FLSs. Micro-CT and immunofluorescence were performed to determine if IL-13 can induce OPG expression and alleviate bone erosion in vivo.
RESULTS
IL-13 can promote OPG expression of RA-FLSs, and the promotion can be overcome by IL-13Rα1 or IL-13Rα2 siRNA transfection, or STAT6 inhibitor. Osteoclast differentiation can be inhibited by IL-13 pre-treated RA-FLSs conditioned medium. The inhibition can be reversed by OPG siRNA transfection. IL-13 injection can increase OPG expression in the joints while reducing bone destruction in collagen-induced arthritis mice.
CONCLUSIONS
IL-13 can inhibit osteoclastogenesis by up-regulating OPG in RA-FLSs through IL-13 receptors via the STAT6 pathway, thus may ameliorate bone erosion in RA.
Topics: Animals; Mice; Synoviocytes; Interleukin-13; Osteoprotegerin; Culture Media, Conditioned; Arthritis, Rheumatoid; Osteoclasts; Cytokines; Fibroblasts; Receptors, Interleukin-13; RNA, Small Interfering; RANK Ligand; Cells, Cultured
PubMed: 36995338
DOI: 10.55563/clinexprheumatol/b96n1e -
Cell Biology International Jun 2024Type 2 diabetic osteoporosis (T2DOP) is a skeletal metabolic syndrome characterized by impaired bone remodeling due to type 2 diabetes mellitus, and there are drawbacks...
Type 2 diabetic osteoporosis (T2DOP) is a skeletal metabolic syndrome characterized by impaired bone remodeling due to type 2 diabetes mellitus, and there are drawbacks in the present treatment. Osteoking (OK) is widely used for treating fractures and femoral head necrosis. However, OK is seldom reported in the field of T2DOP, and its role and mechanism of action need to be elucidated. Consequently, this study investigated whether OK improves bone remodeling and the mechanisms of diabetes-induced injury. We used db/db mice as a T2DOP model and stimulated MC3T3-E1 cells (osteoblast cell line) with high glucose (HG, 50 mM) and advanced glycation end products (AGEs, 100 µg/mL), respectively. The effect of OK on T2DOP was assessed using a combined 3-point mechanical bending test, hematoxylin and eosin staining, and enzyme-linked immunosorbent assay. The effect of OK on enhancing MC3T3-E1 cell differentiation and mineralization under HG and AGEs conditions was assessed by an alkaline phosphatase activity assay and alizarin red S staining. The AGEs/insulin-like growth factor-1(IGF-1)/β-catenin/osteoprotegerin (OPG) pathway-associated protein levels were assayed by western blot analysis and immunohistochemical staining. We found that OK reduced hyperglycemia, attenuated bone damage, repaired bone remodeling, increased tibial and femoral IGF-1, β-catenin, and OPG expression, and decreased receptor activator of nuclear kappa B ligand and receptor activator of nuclear kappa B expression in db/db mice. Moreover, OK promoted the differentiation and mineralization of MC3T3-E1 cells under HG and AGEs conditions, respectively, and regulated the levels of AGEs/IGF-1/β-catenin/OPG pathway-associated proteins. In conclusion, our results suggest that OK may lower blood glucose, alleviate bone damage, and attenuate T2DOP, in part through activation of the AGEs/IGF-1/β-catenin/OPG pathway.
PubMed: 38937979
DOI: 10.1002/cbin.12215 -
Archives of Oral Biology Feb 2024Leptin receptor-positive (LepR) periodontal ligament (PDL) cells play a crucial role in osteogenesis during tooth socket healing and orthodontic tooth movement; however,...
OBJECTIVE
Leptin receptor-positive (LepR) periodontal ligament (PDL) cells play a crucial role in osteogenesis during tooth socket healing and orthodontic tooth movement; however, the factors regulating osteoblast differentiation remain unclear. This study aimed to demonstrate the function of low-density lipoprotein receptor-related protein 1 (LRP1) in alveolar bone formation by examining conditional knockout (cKO) mice lacking LRP1 in LepR cells.
DESIGN
Bone mass and formation were examined via bone morphometric analysis. Bone formation and resorption activities were determined via histochemical staining. Additionally, PDL cells collected from molars were induced to differentiate into osteoblasts with the addition of BMP2 and to mineralize with the addition of osteogenic medium. Osteoblast differentiation of PDL cells was examined by measuring the expression of osteoblast markers.
RESULTS
Bone morphometry analysis revealed decreased mineral apposition rate and alveolar bone mass in cKO mice. Additionally, cKO mice showed a decreased number of osterix-positive cells in the PDL. cKO mice had a large number of osteoclasts around the alveolar bone near the root apex and mesial surface of the tooth. In the PDL cells from cKO mice, inhibition of mineralized matrix formation and decreased expression of alkaline phosphatase, osterix, bone sialoprotein, and osteocalcin were observed even when BMP2 was added to the medium. BMP2, BMP4, and osteoprotegerin expression also decreased, but RANKL expression increased dominantly.
CONCLUSION
LRP1 in LepR cells promotes bone formation by stimulating osteoblast differentiation. Our findings can contribute to clinical research on bone diseases and help elucidate bone metabolism in the periodontal tissue.
Topics: Animals; Mice; Cell Differentiation; Osteoclasts; Osteogenesis; Periodontal Ligament; Periodontium; Receptors, Leptin
PubMed: 38041876
DOI: 10.1016/j.archoralbio.2023.105853 -
Journal of Periodontal Research Jun 2024Psychological stress is a potential modifiable environmental risk factor causally related to the exacerbation of periodontitis and other chronic inflammatory diseases....
OBJECTIVE AND BACKGROUND
Psychological stress is a potential modifiable environmental risk factor causally related to the exacerbation of periodontitis and other chronic inflammatory diseases. This animal study aimed to investigate comprehensively the preventive efficacy of systemic melatonin administration on the possible effects of restraint stress on the periodontal structures of rats with periodontitis.
METHODS
Forty-eight male Sprague Dawley rats were randomly divided into six groups: control, restraint stress (S), S-melatonin (S-Mel), experimental periodontitis (Ep), S-Ep, and S-Ep-Mel. Periodontitis was induced by placing a 3.0 silk suture in a sub-paramarginal position around the cervix of the right and left lower first molars of the rats and keeping the suture in place for 5 weeks. Restraint stress was applied simultaneously by ligation. Melatonin and carriers were administered to the control, S, Ep, and S-Ep groups intraperitoneally (10 mg/body weight/day, 14 days) starting on day 21 following ligation and subjection to restraint stress. An open field test was performed on all groups on day 35 of the study. Periodontal bone loss was measured via histological sections. Histomorphometric and immunohistochemical (RANKL and OPG) evaluations were performed on right mandibular tissue samples and biochemical (TOS (total oxidant status), TAS (total antioxidant status), OSI (oxidative stress index), IL-1β, IL-10, and IL-1β/IL-10) evaluations were performed on left mandibular tissue samples.
RESULTS
Melatonin significantly limited serum corticosterone elevation related to restraint stress (p < .05). Restraint stress aggravated alveolar bone loss in rats with periodontitis, while systemic melatonin administration significantly reduced stress-related periodontal bone loss. According to the biochemical analyses, melatonin significantly lowered IL-1β/IL-10, OSI (TOS/TAS), and RANKL/OPG rates, which were significantly elevated in the S-Ep group.
CONCLUSION
Melatonin can significantly prevent the limited destructive effects of stress on periodontal tissues by suppressing RANKL-related osteoclastogenesis and oxidative stress.
Topics: Animals; Melatonin; Periodontitis; Stress, Psychological; Male; Rats, Sprague-Dawley; Rats; Alveolar Bone Loss; Antioxidants; Disease Models, Animal; RANK Ligand; Oxidative Stress; Random Allocation; Restraint, Physical; Osteoprotegerin
PubMed: 38214233
DOI: 10.1111/jre.13231 -
Advanced Healthcare Materials Jun 2024Precision material design directed by cell biological processes represents a frontier in developing clinically translatable regenerative technologies. While...
Precision material design directed by cell biological processes represents a frontier in developing clinically translatable regenerative technologies. While understanding cell-material interactions on multipotent progenitor cells yields insights on target tissue differentiation, equally if not more important is the quantification of indirect multicellular interactions. In this work, the relationship of two material properties, phosphate content and stiffness, of a nanoparticulate mineralized collagen glycosaminoglycan scaffold (MC-GAG) in the expression of an endogenous anti-osteoclastogenic secreted protein, osteoprotegerin (OPG) by primary human mesenchymal stem cells (hMSCs) is evaluated. The phosphate content of MC-GAG requires the type III sodium phosphate symporter PiT-1/SLC20A1 for OPG expression, correlating with β-catenin downregulation, but is independent of the effects of phosphate ion on osteogenic differentiation. Using three stiffness MC-GAG variants that do not differ significantly by osteogenic differentiation, it is observed that the softest material elicited ≈1.6-2 times higher OPG expression than the stiffer materials. Knockdown of the mechanosensitive signaling axis of YAP, TAZ, β-catenin and combinations thereof in hMSCs on MC-GAG demonstrates that β-catenin downregulation increases OPG expression by 1.5-fold. Taken together, these data constitute a roadmap for material properties that can used to suppress osteoclast activation via osteoprotegerin expression separately from the anabolic processes of osteogenesis.
PubMed: 38885525
DOI: 10.1002/adhm.202401037 -
Drug Delivery and Translational Research Jul 2024Osteoarthritis is a bone and joint condition characterized pathologically by articular cartilage degenerative damage and can develop into a devastating and permanently...
Magnetic targeting of lornoxicam/SPION bilosomes loaded in a thermosensitive in situ hydrogel system for the management of osteoarthritis: Optimization, in vitro, ex vivo, and in vivo studies in rat model via modulation of RANKL/OPG.
Osteoarthritis is a bone and joint condition characterized pathologically by articular cartilage degenerative damage and can develop into a devastating and permanently disabling disorder. This investigation aimed to formulate the anti-inflammatory drug lornoxicam (LOR) into bile salt-enriched vesicles loaded in an in situ forming hydrogel as a potential local treatment of osteoarthritis. This was achieved by formulating LOR-loaded bilosomes that are also loaded with superparamagnetic iron oxide nanoparticles (SPIONs) for intra-muscular (IM) administration to improve joint targeting and localization by applying an external magnet to the joint. A 3.2 full factorial design was employed to develop the bilosomal dispersions and the optimized formula including SPION (LSB) was loaded into a thermosensitive hydrogel. Moreover, in vivo evaluation revealed that the IM administration of LSB combined with the application of an external magnet to the joint reversed carrageen-induced suppression in motor activity and osteoprotegerin by significantly reducing the elevations in mitogen-activated protein kinases, extracellular signal-regulated kinase, and receptor activator of nuclear factor kappa beta/osteoprotegerin expressions. In addition, the histopathological evaluation of knee joint tissues showed a remarkable improvement in the injured joint tissues. The results proved that the developed LSB could be a promising IM drug delivery system for osteoarthritis management.
Topics: Animals; Osteoarthritis; Hydrogels; Piroxicam; Male; RANK Ligand; Rats; Magnetic Iron Oxide Nanoparticles; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Liposomes; Rats, Wistar; Drug Delivery Systems
PubMed: 38158473
DOI: 10.1007/s13346-023-01503-8 -
Biomedicines May 2024The global incidence of Type 2 diabetes (T2D) is on the rise, fueled by factors such as obesity, sedentary lifestyles, socio-economic factors, and ethnic backgrounds....
Ethnic Variations in the Levels of Bone Biomarkers (Osteoprostegerin, Receptor Activator of Nuclear Factor Kappa-Β Ligand and Glycoprotein Non-Metastatic Melanoma Protein B) in People with Type 2 Diabetes.
The global incidence of Type 2 diabetes (T2D) is on the rise, fueled by factors such as obesity, sedentary lifestyles, socio-economic factors, and ethnic backgrounds. T2D is a multifaceted condition often associated with various health complications, including adverse effects on bone health. This study aims to assess key biomarkers linked to bone health and remodeling-Osteoprotegerin (OPG), Receptor Activator of Nuclear Factor Kappa-Β Ligand (RANKL), and Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB)-among individuals with diabetes while exploring the impact of ethnicity on these biomarkers. A cross-sectional analysis was conducted on a cohort of 2083 individuals from diverse ethnic backgrounds residing in Kuwait. The results indicate significantly elevated levels of these markers in individuals with T2D compared to non-diabetic counterparts, with OPG at 826.47 (405.8) pg/mL, RANKL at 9.25 (17.3) pg/mL, and GPNMB at 21.44 (7) ng/mL versus 653.75 (231.7) pg/mL, 0.21 (9.94) pg/mL, and 18.65 (5) ng/mL in non-diabetic individuals, respectively. Notably, this elevation was consistent across Arab and Asian populations, except for lower levels of RANKL observed in Arabs with T2D. Furthermore, a positive and significant correlation between OPG and GPNMB was observed regardless of ethnicity or diabetes status, with the strongest correlation (r = 0.473, < 0.001) found among Arab individuals with T2D. Similarly, a positive and significant correlation between GPNMB and RANKL was noted among Asian individuals with T2D (r = 0.401, = 0.001). Interestingly, a significant inverse correlation was detected between OPG and RANKL in non-diabetic Arab individuals. These findings highlight dysregulation in bone remodeling markers among individuals with T2D and emphasize the importance of considering ethnic variations in T2D-related complications. The performance of further studies is warranted to understand the underlying mechanisms and develop interventions based on ethnicity for personalized treatment approaches.
PubMed: 38790981
DOI: 10.3390/biomedicines12051019 -
Blood Pressure Monitoring Apr 2024Past studies have shown that non-dipper hypertensive patients have more frequent subclinical left ventricular (LV) systolic dysfunction compared to dippers. Many...
BACKGROUND
Past studies have shown that non-dipper hypertensive patients have more frequent subclinical left ventricular (LV) systolic dysfunction compared to dippers. Many different parameters have been examined to predict subclinical LV dysfunction. The role of osteoprotegerin (OPG) in the pathogenesis of heart failure and LV systolic dysfunction through different mechanisms had well described. In the present study, we hypothesized that increased OPG levels could predict subclinical LV systolic dysfunction in non-dipper hypertensive patients.
PATIENTS AND METHODS
Hypertensive patients were divided into two groups according to the results of ambulatory blood pressure (BP) monitoring. Non-dipper patients were subsequently divided into two further groups (normal LV function and impaired LV function) according to LV global longitudinal strain (GLS).
RESULTS
A total of 103 hypertensive patients (51 dippers, 52 non-dippers) were included in the study. In the non-dipper group, LV GLS was normal in 21 patients and impaired in 31 patients. Based on the results of the multivariate logistic regression test, it was determined that OPG levels (OR: 2.413, 95% CI: 1.284-4.535, P = 0.006) and LVMI (OR: 1.086, 95% CI: 1.013-1.165, P = 0.021) were independently associated with impaired GLS.
CONCLUSION
Higher OPG values were associated with subclinical LV systolic dysfunction in non-dipper hypertensive patients. It could be used for the early diagnosis of subclinical LV systolic dysfunction, which would allow for strategies to be designed to reduce the cardiovascular event rate in this patient population.
Topics: Humans; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Echocardiography; Hypertension; Osteoprotegerin; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Function, Left
PubMed: 37937620
DOI: 10.1097/MBP.0000000000000681