Induce Bone Resorption Research Articles

Sexual dimorphism of MASLD-driven bone loss.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is highly prevalent with major risk of progression to Metabolic Dysfunction-Associated Steatohepatitis (MASH) and Hepatocellular Carcinoma (HCC). Recently, osteoporosis and bone fracture have emerged as sexually-dimorphic comorbidities of MASLD yet the mechanisms of this bone loss are unknown. Herein, we address these knowledge gaps using DIAMOND mice which develop MASLD, MASH, and HCC via Western diet exposure. We examined the skeletal phenotype of male DIAMOND mice after 16, 36, and 48 weeks of exposure to Western or control diet. At 16 weeks, male DIAMOND mice with MASLD lose trabecular bone but retain mechanical bone integrity. At 48 weeks, males lose cortical bone and mechanical integrity, indicating severe skeletal weakening. Female DIAMOND mice were protected from cortical and trabecular MASLD-associated bone loss and skeletal fragility at all timepoints. Using NicheNet, a publicly available database of hepatic mRNA expression in DIAMOND mice, and a PTH-induced model of bone loss, we suggest Ctgf, Rarres2, Anxa2, Fgf21, and Mmp13 are liver-secreted ligands inducing bone resorption. This study is the first preclinical investigation of bone loss in MASLD, and the first to suggest the role of Ctgf, Rarrest2, Anxa2, Fgf21, and Mmp13 as drivers of this pathology.

Inhibitory impact of a mesoporous silica nanoparticle-based drug delivery system on Porphyromonas gingivalis-induced bone resorption

Controlling and reducing plaque formation plays a pivotal role in preventing and treating periodontal disease, often utilizing antibacterial drugs to enhance therapeutic outcomes. Mesoporous silica nanoparticles (MSN), an FDA-approved inorganic nanomaterial, possess robust physical and chemical properties, such as adjustable pore size and pore capacity, easy surface modification, and high biosafety. Numerous studies have exploited MSN to regulate drug release and facilitate targeted delivery. This study aimed to synthesize an MSN-tetracycline (MSN-TC) complex and investigate its inhibitory potential on Porphyromonas gingivalis (P. gingivalis)-induced bone resorption. The antibacterial efficacy of MSN-TC was evaluated through bacterial culture experiments. A P. gingivalis-induced bone resorption model was constructed by subcutaneously injecting P. gingivalis around the cranial bone of rats. Micro-computed tomography was employed to assess the inhibitory impact of MSN and MSN-TC on bone resorption. Furthermore, the influence of MSN and MSN-TC on osteoclast differentiation was examined in vitro. The MSN exhibited optimal pore size and particle dimensions for effective loading and gradual release of TC. MSN-TC demonstrated significant bacteriostatic activity against P. gingivalis. MSN-TC-treated rats showed significantly reduced cranial bone tissue destruction compared to MSN or TC-treated rats. Additionally, both MSN and MSN-TC exhibited inhibitory effects on the receptor activator of nuclear factor kappa-Β ligand-mediated osteoclast differentiation. The MSN-TC complex synthesized in this study demonstrated dual efficacy by exerting antibacterial effects on P. gingivalis and by resisting osteoclast differentiation, thereby mitigating bone resorption induced by P. gingivalis.Graphical

Factors Influencing Bone Resorption after Augmentation Mentoplasty with Implants: A Retrospective Study Using Three-Dimensional Imaging.

Augmentation mentoplasty with implants is an extremely rewarding procedure. Bone resorption is almost unavoidable. The high-risk factors for chin bone resorption have not been explored in the past. This study aimed to analyze and evaluate the factors influencing bone resorption after augmentation mentoplasty with implants using three-dimensional imaging. We retrospectively analyzed preoperative craniofacial Computed Tomography scan data from 105 patients who underwent mandibular implantation surgery and 108 patients who did not. We also examined the extent to which different factors influenced the occurrence of bone resorption in the chin area. Patients with silicone gel implants are more prone to bone resorption than those with Medpor implants. Patients who experienced bone resorption had thicker mentalis muscles than those who did not experience bone resorption (6.35 ± 1.mm vs. 5.73 ± 1.25mm, P < 0.05), and thinner cortical bone (3.25 ± 1.65mm vs. 5.22 ± 2.04 mm, P < 0.05). Additionally, implants placed above the mandibular bone were more likely to induce bone resorption than those placed below it. This study is the first to systematically reveal the impact of implant type, placement position, mentalis muscle thickness, and cortical bone thickness on bone resorption after chin augmentation surgery. For patients with thicker mentalis muscles and thinner cortical bones, greater attention should be paid to the occurrence of bone resorption. Choosing silicone implants or placing the implants higher on the mandible can help reduce the occurrence of bone resorption. This study can assist clinicians in selecting appropriate treatment methods, thereby reducing post-implantation bone resorption. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Ammonia exposure impairs bone mineralization in zebrafish (Danio rerio) larvae

Ammonia is a major pollutant of freshwater environments. Previous studies have indicated that ammonia exposure adversely affects the physiology of freshwater fish. However, its effect on bone mineralization in freshwater fish larvae remains unclear. In this study, zebrafish larvae were used as a model to investigate the effects of different ammonia levels (0, 2.5, 5, and 10 mM NH4Cl) on the survival rate, body length, and bone mineralization of fish. The survival rate of zebrafish embryos exposed to different NH4Cl concentrations for 8 days was not affected. In contrast, the body length and bone mineralization of zebrafish larvae at 8 days post fertilization (dpf) were significantly reduced at 5 and 10 mM NH4Cl exposure. Further investigations revealed that ammonia exposure decreased the mRNA expression of osteoblast-related genes and increased that of osteoclast-related genes. Additionally, exposure to 5 mM and 10 mM NH4Cl induced the production of reactive oxygen species (ROS). 10 mM—but not 5 mM—NH4Cl exposure reduced the calcium and phosphorus content in 8 dpf zebrafish larvae. In conclusion, ammonia exposure induces bone resorption, while decreasing the calcium and phosphorus content of the whole body and bone formation, resulting in impaired bone mineralization in fish larvae.

Heat-killed Lancefieldella Rimae Induces Bone Resorption by Promoting Osteoclast Differentiation

IntroductionApical periodontitis, mainly caused by bacterial infection in the dental pulp, is often accompanied by abscess, periapical inflammation, and alveolar bone loss. Lancefieldella rimae has been detected in the root canals of patients with apical periodontitis. Here, we investigated whether L. rimae is associated with bone resorption. MethodsL. rimae was anaerobically cultured and heat-killed (HKLr). A mouse calvarial implantation model was used to determine the bone resorption in vivo. Committed osteoclasts prepared from C57BL/6 wild-type or Toll-like receptor 2 (TLR2)-deficient mice were differentiated into mature osteoclasts in the presence or absence of HKLr. The mRNA expression of tartrate-resistant acid phosphatase (TRAP), ATPase H+ transporting V0 subunit D2, cathepsin K, interleukin-6, tumor necrosis factor-α, and glyceraldehyde 3-phosphate dehydrogenase was quantified using real-time reverse transcription-polymerase chain reaction. The protein levels of c-Fos and NFATc1 were determined by Western blot analysis. ResultsImplantation of HKLr onto the mouse calvaria induced the bone destruction with an increase of TRAP-positive areas. While HKLr enhanced the differentiation of osteoclasts, this effect was not observed in TLR2-deficient osteoclasts. HKLr dose-dependently increased the mRNA expression of genes associated with osteoclast differentiation including TRAP, ATPase H+ transporting V0 subunit D2, and cathepsin K. In addition, HKLr enhanced the expression of c-Fos and NFATc1, which are important transcription factors for osteoclast differentiation. Moreover, HKLr increased the expression of interleukin-6 and tumor necrosis factor-α. ConclusionL. rimae induces bone resorption by enhancing osteoclast differentiation through the TLR2 signaling pathway, implying that L. rimae is a causative agent responsible for the alveolar bone resorption accompanying apical periodontitis.

Sclerostin blockade inhibits bone resorption through PDGF receptor signaling in osteoblast lineage cells.

While sclerostin-neutralizing antibodies (Scl-Abs) transiently stimulate bone formation by activating Wnt signaling in osteoblast lineage cells, they exert sustained inhibition of bone resorption, suggesting an alternate signaling pathway by which Scl-Abs control osteoclast activity. Since sclerostin can activate platelet-derived growth factor receptors (PDGFRs) in osteoblast lineage cells in vitro and PDGFR signaling in these cells induces bone resorption through M-CSF secretion, we hypothesized that the prolonged anticatabolic effect of Scl-Abs could result from PDGFR inhibition. We show here that inhibition of PDGFR signaling in osteoblast lineage cells is sufficient and necessary to mediate prolonged Scl-Ab effects on M-CSF secretion and osteoclast activity in mice. Indeed, sclerostin coactivates PDGFRs independently of Wnt/β-catenin signaling inhibition, by forming a ternary complex with LRP6 and PDGFRs in preosteoblasts. In turn, Scl-Ab prevents sclerostin-mediated coactivation of PDGFR signaling and consequent M-CSF upregulation in preosteoblast cultures, thereby inhibiting osteoclast activity in preosteoblast/osteoclast coculture assays. These results provide a potential mechanism explaining the dissociation between anabolic and antiresorptive effects of long-term Scl-Ab.

Vibration Rather than Microgravity Affects Bone Metabolism in Adult Zebrafish Scale Model.

Gravity and mechanical forces cause important alterations in the human skeletal system, as demonstrated by space flights. Innovative animal models like zebrafish embryos and medaka have been introduced to study bone response in ground-based microgravity simulators. We used, for the first time, adult zebrafish in simulated microgravity, with a random positioning machine (RPM) to study bone remodeling in the scales. To evaluate the effects of microgravity on bone remodeling in adult bone tissue, we exposed adult zebrafish to microgravity for 14 days using RPM and we evaluated bone remodeling on explanted scales. Our data highlight bone resorption in scales in simulated microgravity fish but also in the fish exposed, in normal gravity, to the vibrations produced by the RPM. The osteoclast activation in both rotating and non-rotating samples suggest that prolonged vibrations exposure leads to bone resorption in the scales tissue. Stress levels in these fish were normal, as demonstrated by blood cortisol quantification. In conclusion, vibrational mechanical stress induced bone resorption in adult fish scales. Moreover, adult fish as an animal model for microgravity studies remains controversial since fish usually live in weightless conditions because of the buoyant force from water and do not constantly need to support their bodies against gravity.

Aseptic Silk Ligatures Induce Bone Resorption Around Titanium Implants: A 12-Week Pilot Study in Rabbits.

Marginal bone resorption (MBR) around dental implants may sometimes be a self-limiting condition due to balancing immunologic reactions against utilized materials rather than a progressive bacterial infection. Contrary to previous assumptions from ligature-induced experimental peri-implantitis studies, a recent 8-week experiment by the present authors showed that marginal ligatures trigger an inflammatory immune response, resulting in bone resorption around implants in the absence of plaque. The present study aimed to investigate whether this inflammatory/immunologic reaction attenuates or progresses toward implant failure after a longer healing time (12 weeks). Sterile silk ligatures were placed around the top of titanium (Ti) implants and compressed against the femoral cortical bone plate of six rabbits. A nonligated implant was used as a control. After 12 weeks of submerged healing, ground sections of implants and surrounding tissues were investigated with light microscopy. The marginal soft tissues were also analyzed using selected quantitative polymerase chain reaction (qPCR) markers. Histologically, the ligatures were outlined by immune cells, including multinucleated giant cells (MNGCs), with adjacent fibrous encapsulation and resorbed peripheral bone that contrasted from the osseointegrated nonligated control implants. The difference in expression of qPCR markers was not significant, but > two-fold upregulation of markers CD11b, IL1β, ARG1, NCF1, and CD4 and > twofold downregulation of CD8 indicated a mild, focal inflammatory/immune response against the ligatures compared to controls, with upregulation of M1 and M2 macrophages, neutrophils, and helper T-cells as well as downregulation of killer T cells. Further, the bone formation markers OC and ALPL were > two-fold downregulated (consistent with the lack of osseointegration of the ligatures) compared to control implants. Marginal silk ligatures trigger an inflammatory/immune response and aseptic bone resorption around implants. Compared to the previous 8-week study, the inflammatory reaction against the silk appears to attenuate with time, with only a mild persisting inflammation that may block osseointegration; instead, a fibrous tissue encapsulation-type reaction is maintained. This may explain why traditional ligature experiments have required regular exchange of ligatures for the bone resorption to progress.

Non-biofilm-forming Staphylococcus epidermidis planktonic cell supernatant induces alterations in osteoblast biological function

Staphylococcal biofilms significantly contribute to prosthetic joint infection (PJI). However, 40% of S. epidermidis PJI isolates do not produce biofilms, which does not explain the role of biofilms in these cases. We studied whether the supernatant from planktonic S. epidermidis alters osteoblast function. Non-biofilm-forming S. epidermidis supernatants (PJI− clinical isolate, healthy skin isolate (HS), and ATCC12228 reference strain) and biofilm-forming supernatants (PJI+ clinical isolate, ATCC35984 reference strain, and Staphylococcus aureus USA300 reference strain) were included. Osteoblasts stimulated with supernatants from non-biofilm-forming isolates for 3, 7, and 14 days showed significantly reduced cellular DNA content compared with unstimulated osteoblasts, and apoptosis was induced in these osteoblasts. Similar results were obtained for biofilm-forming isolates, but with a greater reduction in DNA content and higher apoptosis. Alkaline phosphatase activity and mineralization were significantly reduced in osteoblasts treated with supernatants from non-biofilm-forming isolates compared to the control at the same time points. However, the supernatants from biofilm-forming isolates had a greater effect than those from non-biofilm-forming isolates. A significant decrease in the expression of ATF4, RUNX2, ALP, SPARC, and BGLAP, and a significant increase in RANK-L expression were observed in osteoblasts treated with both supernatants. These results demonstrate that the supernatants of the S. epidermidis isolate from the PJI− and HS (commensal) with a non-biofilm-forming phenotype alter the function of osteoblasts (apoptosis induction, failure of cell differentiation, activation of osteoblasts, and induction of bone resorption), similar to biofilm-forming isolates (PJI+, ATCC35984, and S. aureus USA300), suggesting that biofilm status contributes to impaired osteoblast function and that the planktonic state can do so independently of biofilm production.

The Lymphatic Endothelial Cell Secretome Inhibits Osteoblast Differentiation and Bone Formation.

Complex lymphatic anomalies (CLAs) are a set of rare diseases with unique osteopathic profiles. Recent efforts have identified how lymphatic-specific somatic activating mutations can induce abnormal lymphatic formations that are capable of invading bone and inducing bone resorption. The abnormal bone resorption in CLA patients has been linked to overactive osteoclasts in areas with lymphatic invasions. Despite these findings, the mechanism associated with progressive bone loss in CLAs remains to be elucidated. In order to determine the role of osteoblasts in CLAs, we sought to assess osteoblast differentiation and bone formation when exposed to the lymphatic endothelial cell secretome. When treated with lymphatic endothelial cell conditioned medium (L-CM), osteoblasts exhibited a significant decrease in proliferation, differentiation, and function. Additionally, L-CM treatment also inhibited bone formation through a neonatal calvaria explant culture. These findings are the first to reveal how osteoblasts may be actively suppressed during bone lymphatic invasion in CLAs.

The vitamin D receptor in osteoblastic cells but not secreted parathyroid hormone is crucial for soft tissue calcification induced by the proresorptive activity of 1,25(OH)2D3

The vitamin D receptor (VDR) is expressed most abundantly in osteoblasts and osteocytes (osteoblastic cells) in bone tissues and regulates bone resorption and calcium (Ca) and phosphate (P) homeostasis in association with parathyroid hormone (PTH). We previously reported that near-physiological doses of vitamin D compounds suppressed bone resorption through VDR in osteoblastic cells. We also found that supra-physiological doses of 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] induced bone resorption and hypercalcemia via VDR in osteoblastic cells. Here, we report that the latter, a proresorptive dose of 1,25(OH)2D3, causes soft tissue calcification through VDR in osteoblastic cells. High concentrations of vitamin D affect multiple organs and cause soft tissue calcification, with increases in bone resorption and serum Ca levels. Such a variety of symptoms is known as hypervitaminosis D, which is caused by not only high doses of vitamin D but also impaired vitamin D metabolism and diseases that produce 1,25(OH)2D3 ectopically. To clarify the biological process hierarchy in hypervitaminosis D, a proresorptive dose of 1,25(OH)2D3 was administered to wild-type mice in which bone resorption had been suppressed by neutralizing anti-receptor activator of NF-κB ligand (RANKL) antibody. 1,25(OH)2D3 upregulated the serum Ca x P product, concomitantly induced calcification of the aorta, lungs, and kidneys, and downregulated serum PTH levels in control IgG-pretreated wild-type mice. Pretreatment of wild-type mice with anti-RANKL antibody did not affect the down-regulation of PTH levels by 1,25(OH)2D3, but inhibited the increase of the serum Ca x P product and soft tissue calcification induced by 1,25(OH)2D3. Consistent with the effects of anti-RANKL antibody, VDR ablation in osteoblastic cells also did not affect the down-regulation of PTH levels by 1,25(OH)2D3, but suppressed the 1,25(OH)2D3-induced increase of the serum Ca x P product and calcification of soft tissues. Taken together with our previous results, these findings suggest that bone resorption induced by VDR signaling in osteoblastic cells is critical for the pathogenesis of hypervitaminosis D, but PTH is not involved in hypervitaminosis D.

Expression of Stro-1, Runx-2, Osterix, and Alp in Alveolar Bone Regeneration Process Following the Administration of Hydroxyapatite Gypsum Puger (HAGP) Scaffold

Introduction: Tooth extraction before denture placement could result in trauma and damage to up to 50% of the alveolar bone, inducing bone resorption, and affecting the patient’s quality of life. Hydroxyapatite Gypsum Puger (HAGP) can be used as an alternative to bone graft material which degrades slowly, affecting the proliferation and activity of cells that are responsible for bone tissue engineering. This study aimed to analyze the regeneration mechanism of alveolar bone by administering the HAGP scaffold and observing the Stro-1, Runx-2, Osterix, and ALP expression. Methods: Laboratory experimental research was conducted and we used 150-355µm HAGP scaffold particles, applied in vivo inside alveolar sockets of the rats for 7, 14, and 28 days, followed by immunohistochemical examination of Stro-1, Runx-2, Osterix, and ALP expressions. Results: The HAGP scaffold group showed that the Stro-1 expression was significantly higher than the K(-) group, and the Runx-2 expression increased on day 7 and decreased on day 28 in the HAGP and K(-) groups. Osterix expression increased from day 7, 14, to day 28. The high expression of Osterix on day 28 means it took over the Runx-2 function. In ALP there was a significant increase on day 7. ALP expression was a sign of early osteoblast differentiation and production by cells, this extracellular matrix mineralization is an indicator of the osteogenic process. Conclusion: Alveolar bone regeneration mechanism in rats revealed that the expression of Stro-1, Runx-2, Osterix, and ALP was higher in the HAGP scaffold group compared to the control group on days 7,14, and 28.

Recent advances of osteoimmunology research in rheumatoid arthritis: From single-cell omics approach.

Cellular immune responses as well as generalized and periarticular bone loss are the key pathogenic features of rheumatoid arthritis (RA). Under the pathological conditions of RA, dysregulated inflammation and immune processes tightly interact with skeletal system, resulting in pathological bone damage via inhibition of bone formation or induction of bone resorption. Single-cell omics technologies are revolutionary tools in the field of modern biological research.They enable the display of the state and function of cells in various environments from a single-cell resolution, thus making it conducive to identify the dysregulated molecular mechanisms of bone destruction in RA as well as the discovery of potential therapeutic targets and biomarkers. Here, we summarize the latest findings of single-cell omics technologies in osteoimmunology research in RA. These results suggest that single-cell omics have made significant contributions to transcriptomics and dynamics of specific cells involved in bone remodeling, providing a new direction for our understanding of cellular heterogeneity in the study of osteoimmunology in RA.

Design of a functionally graded porous uncemented acetabular component: Influence of polar gradation.

The functionally graded porous metal-backed (FGPMB) acetabular component has the potential to minimize strain-shielding induced bone resorption, caused by stiffness mismatch of implant and host bone. This study is aimed at a novel design of FGPMB acetabular component, which is based on numerical investigations of the mechanical behavior of acetabular components with regard to common failure scenarios, considering various daily activities and implant-bone interface conditions. Both radial and polar functional gradations were implemented, and the effects of the polar gradation exponent on the failure criteria were evaluated. The relationships between porosity and orthotropic mechanical properties of a tetrahedron-based unit cell were obtained using a numerical homogenization method. Strain-shielding in cancellous bone was relatively lesser for the FGPMB than solid metal-backing. Few nodes around the rim were susceptible to implant-bone interfacial debonding, irrespective of the polar gradation exponent. Although the most favorable bone remodeling predictions were obtained for a polar gradation exponent of 0.1, a sudden change in the porosity was observed near the rim of FGPMB. Bone remodeling patterns were similar for polar gradation exponent of 5.0 and solid metal-backing. Moreover, the volumetric wear was maximum and minimum for polar gradation exponents of 0.1 and 5, respectively. Furthermore, the micromotions of different polar gradation exponents were within a range (20-40 μm) that might facilitate bone ingrowth. Considering common failure mechanisms, the FGPMB having polar gradation exponents in the range of 0.1-0.5 appeared to be a viable alternative to the solid acetabular component, within which a gradation exponent of 0.25 seemed the most appropriate design parameter.

Recent Advances in Apical Periodontitis Treatment: A Narrative Review.

Apical periodontitis is an inflammatory response caused by pulp infection. It induces bone resorption in the apical and periapical regions of the tooth. The most conservative approach to treat this condition is nonsurgical endodontic treatment. However, clinical failure has been reported with this approach; thus, alternative procedures are required. This review highlights recent literature regarding advanced approaches for the treatment of apical periodontitis. Various therapies, including biological medications, antioxidants, specialized pro-resolving lipid mediators, and stem cell therapy, have been tested to increase the success rate of treatment for apical periodontitis. Some of these approaches remain in the in vivo phase of research, while others have just entered the translational research phase to validate clinical application. However, a detailed understanding of the molecular mechanisms that occur during development of the immunoinflammatory reaction in apical periodontitis remains unclear. The aim of this review was to summarize advanced approaches for the treatment of apical periodontitis. Further research can confirm the potential of these alternative nonsurgical endodontic treatment approaches.

Abstract 1603: The effect of dickkopf-1 (DKK-1) on prostate cancer growth and bone metastasis using the canine osteoblastic Probasco cell line

Abstract Osteoblastic bone metastasis is the predominant phenotype observed in advanced prostate cancer and is associated with high patient mortality and morbidity. WNT signaling is necessary for both bone formation and tumor progression. Dickkopf-1 (DKK-1), a secretory antagonist of the canonical WNT/β-catenin signaling pathway, plays a complex role in bone tumors since it can either promote or decrease tumor occurrence and metastasis. The present study explored the molecular role of DKK-1 in prostate tumor progression, metastasis, and tumor-bone interactions using the osteoblastic canine prostate cancer cell line, Probasco. Previously, we found that DKK-1 can inhibit bone mineralization of mouse calvaria by Probasco conditioned medium (CM). Now we stably expressed DKK-1 in Probasco cells (Probasco-DKK-1), which were injected into the tibias or left ventricle of athymic mice. Bone metastases were monitored by bioluminesent imaging, microCT, and histopathology. Our results showed that Probasco-DKK-1 bone metastases had increased tumor growth, increased osteoclastic bone resorption, and decreased intramedullary woven bone formation in vivo. In vitro, DKK-1 had an autocrine effect on Probasco cells, which altered the cell morphology, increased cell proliferation, and induced EMT. Mechanistically, DKK-1 had little effect on the canonical WNT/β-catenin signaling while dramatically down-regulated the non-canonical WNT/JNK signaling, which inhibited caspase-dependent apoptosis in Probasco-DKK-1 cells. To investigate the effect of Probasco-DKK-1 on bone cells, primary osteoblasts and osteoclasts were treated by CM collected from cancer cells. We found that DKK-1 did not inhibit the mineralization of osteoblasts nor stimulate the activity of osteoclasts directly, but the expression of RNAKL was significantly higher in Probasco-DKK-1 CM-treated osteoblasts. Therefore, the Probasco-DKK-1 cells enhanced the activity of osteoclasts indirectly via the regulation of osteoblasts, which induced bone resorption. In conclusion, we showed that DKK-1 promoted prostate tumor growth by stimulating cell proliferation and inhibiting apoptosis in a canonical WNT-independent manner and attenuated the osteoblastic activity of prostate cancer. These findings provide new insights into the molecular mechanisms of DKK-1 in tumor progression. Citation Format: Shiyu Yuan, Nathan K. Hoggard, Noriko Kantake, Blake E. Hildreth, Thomas J. Rosol. The effect of dickkopf-1 (DKK-1) on prostate cancer growth and bone metastasis using the canine osteoblastic Probasco cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1603.

A GP130-Targeting Small Molecule, LMT-28, Reduces LPS-Induced Bone Resorption around Implants in Diabetic Models by Inhibiting IL-6/GP130/JAK2/STAT3 Signaling.

In this study, we examined the effect of the GP130-targeting molecule, LMT-28, on lipopolysaccharide- (LPS-) induced bone resorption around implants in diabetic models using in vitro and rat animal experiments. First, LMT-28 was added to osteoblasts stimulated by LPS and advanced glycation end products (AGEs), and nuclear factor-κB receptor-activating factor ligand (RANKL) and associated pathways were evaluated. Then, LMT-28 was administered by gavage at 0.23 mg/kg once every 5 days for 2 weeks to type 2 diabetic rats with peri-implantitis induced by LPS injection and silk ligature. The expression of IL-6 and RANKL was evaluated by immunohistochemistry, and the bone resorption around implants was evaluated by microcomputed tomography. The results showed that LMT-28 downregulated the expression of RANKL through the JAK2/STAT3 signaling pathway in osteoblasts stimulated by LPS and AGEs, reduced bone resorption around implants with peri-implantitis, decreased the expression of IL-6 and RANKL, and decreased osteoclast activity in type 2 diabetic rats. This study confirmed the ability of LMT-28 to reduce LPS-induced bone resorption around implants in diabetic rats.

Effect of &lt;italic&gt;Spatholobus Suberectus&lt;/italic&gt; Extract (SSE) on RANKL-treated RAW264.7 and LPS-induced Bone Loss

Purpose: We evaluated whether Spatholobus suberectus extract (SSE) can be used as a means of preventing and treating osteoporosis by measuring its effect on osteoclast differentiation, gene expression, and bone resorption.Methods: SSE was used to examine the effect on RAW 264.7 cells stimulated with RANKL to induce bone resorption. The inhibitory effect of TRAP formation and the expression of the bone resorption factors TRAP, cathepsin K, and MMP-9 during differentiation were measured. The effects on the differentiation-related factors NFATc and TRAIL and on the expression of OC-STAMP, DC-STAMP, ATP6v0d2, MITF, c-Fos, and inflammation-related factors were also evaluated. The effect on bone resorption was evaluated by culturing RANKL-treated osteoclasts on artificial bone fragments and observing the resulting resorption traces. The effect on bone damage in experimental animals was also measured.Results: SSE inhibited the differentiation of RANKL-stimulated osteoclasts into osteoclasts and suppressed the expression of cathepsin K, TRAP, MMP-9, NFATc1, TRAIL, MITF, OC-STAMP, DC-STAMP, ATP6v0d2, and c-Fos genes. Bone pore formation due to osteoclast action was also inhibited, and LPS-induced bone loss was suppressed in animal experiments.Conclusions: SSE could be useful for the prevention or treatment of osteoporosis by inhibiting osteoclast differentiation and bone resorption and suppressing bone loss induced in experimental animals. However, studies of larger populations are required.

Cytokine-mediated immunomodulation of osteoclastogenesis.

Cytokines are an important set of proteins regulating bone homeostasis. In inflammation induced bone resorption, cytokines, such as RANKL, TNF-α, M-CSF, are indispensable for the differentiation and activation of resorption-driving osteoclasts, the process we know as osteoclastogenesis. On the other hand, immune system produces a number of regulatory cytokines, including IL-4, IL-10 and IFNs, and limits excessive activation of osteoclastogenesis and bone loss during inflammation. These unique properties make cytokines powerful targets as rheostat to maintain bone homeostasis and for potential immunotherapies of inflammatory bone diseases. In this review, we summarize recent advances in cytokine-mediated regulation of osteoclastogenesis and provide insights of potential translational impact of bench-side research into clinical treatment of bone disease.

Effect of Osteoblast-Specific Deletion of the Proton Receptor OGR1.

Metabolic acidosis (MET) stimulates bone resorption through inhibition of osteoblast (OB) bone formation and stimulation of osteoclast (OC) bone resorption. We found that OGR1, a G protein-coupled proton (H+)-sensing receptor, was critical for initial H+ signaling in the OB. In mice with a global deletion of OGR1, we demonstrated that loss of OGR1 impairs H+-induced bone resorption, leading to increased bone density through effects on both the OB and OC. Using an OC-specific deletion of OGR1, we found that MET directly activates OGR1 in the OC. To determine if the response of OGR1 to MET in the OB is independent of a response in OCs and to characterize direct activation of OGR1 in the OB, we studied female mice with an OB-specific deletion of OGR1 (OB-cKO) and differentiated osteoblasts derived from marrow of OB-cKO and wild-type (WT) mice. In OB-cKO mice, we found increased bone area in both tibial and femoral cortical bone. Specific loss of OB OGR1 increased in vitro mineralization, alkaline phosphatase activity, and expression of osteoblast-specific genes compared with WT with no alteration in OC activity. MET stimulation of OB cox2 and fgf23 gene expression was inhibited in OB-cKO OB. These results indicate that MET activation of OGR1 in the OB is independent of the response in the OC and that OGR1 in both cell types is required for a complete response to MET. Characterization of the role of OGR1 in MET-induced bone resorption will improve our understanding of bone loss associated with metabolic acidosis in patients with chronic kidney disease. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.