Inhibit Bone Destruction Research Articles

Association of denosumab with serum cytokines, chemokines, and bone-related factors in patients with rheumatoid arthritis: A post hoc analysis of a multicentre, open-label, randomised, parallel-group study.

To clarify changes in serum cytokines, chemokines, and bone-related factors during denosumab treatment in rheumatoid arthritis (RA) patients. This was a post hoc analysis of a multicentre, open-label, randomised, parallel-group study. Patients were randomly assigned to continue treatment with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) plus receive treatment with denosumab (csDMARDs plus denosumab group) or to continue treatment with csDMARD therapy alone for 12 months. Serum biomarker levels were measured at baseline and at 6 and 12 months. Baseline and 6-month data from the csDMARDs plus denosumab (n = 22) and csDMARD therapy alone (n = 22) groups were analysed. Statistically significant changes from baseline were seen: Dickkopf-related protein 1 decreased at 6 and 12 months (both groups); osteopontin decreased at 6 months in the csDMARDs plus denosumab group; osteopontin and soluble CD40 ligand increased at 6 and 12 months in the csDMARD therapy alone group; osteocalcin decreased at 6 and 12 months, epidermal growth factor decreased at 12 months, and macrophage-derived chemokine decreased at 6 months in the csDMARDs plus denosumab group; and interferon gamma-induced protein-10 increased at 12 months in the csDMARD therapy alone group. Denosumab may inhibit bone destruction by suppressing bone-related factors/chemokines.

Decipher the pharmacological mechanisms of raw and wine-processed Curculigo orchioides Gaertn. on bone destruction in rheumatoid arthritis rats using metabolomics.

Curculigo orchioides Gaertn. (CO), a traditional Chinese herb recorded in Chinese Pharmacopoeia, can nourish kidney yang, strengthen bones, and dispell cold-dampness. Raw CO (rCO) and wine-processed CO (pCO), the main processed products of CO for clinical application, show differences in nourishing kidney yang and ameliorate osteoporosis. However, the difference in efficacy and mechanism of rCO and pCO on bone destruction in rheumatoid arthritis (RA) remain unclear. To compare the pharmacodynamics of rCO and pCO in the treatment of bone destruction in RA and to reveal the potential mechanism by which rCO and pCO exert effects by metabolomics approach. Ultra-high performance liquid chromatography Q exactive mass spectrometry (UHPLC-Q-Exactive-MS) combined with multivariate data analysis was applied to identify the differential chemical components in rCO and pCO. Collagen-induced arthritis (CIA) rats were orally administrated with different doses of rCO and pCO for 4 weeks. The body weight, paw swelling, arthritis scores, serum inflammatory cytokines concentration, knee tumor necrosis factor (TNF)-α, interleukin (IL)-6 protein levels, and inflammatory cell infiltration were determined to investigate the effects of rCO and pCO on arthritic symptoms and inflammatory responses in CIA rats. The effects of rCO and pCO on bone destruction were assessed using safranin O-fast green and tartrate-resistant acid phosphatase (TRAP) staining, immunohistochemical analysis of osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL) proteins, and micro-computed tomography (micro-CT) in rats. In addition, metabolomics was performed to explore the mechanism of rCO and pCO against bone destruction in RA. A total of 41 chemical constituents were identified in both rCO and pCO, 9 of which were screened out as discriminatory compounds. According to the pharmacodynamic assays, pCO exhibited a stronger effect than rCO in attenuating the severity of arthritis, reducing inflammation, and inhibiting bone destruction. The metabolomics results showed that pentose phosphate pathway was the key metabolic pathways regulated by rCO, while pCO regulated multiple metabolic pathways including phenylalanine metabolism pathways, phenylalanine, tyrosine and tryptophan biosynthesis, taurine and hypotaurine metabolism, and glycerophospholipid metabolism pathways. pCO displayed a better effect on alleviating bone destruction in RA was than rCO. This might be associated with that pCO can decrease inflammation in RA through regulating more metabolism pathways.

Abstract 570: Dual acting bone defender agents inhibit prostate cancer-mediated bone destruction

Abstract Introduction: Bone metastasis is clinically observed in approximately 90% of patients with advanced prostate cancer (PCa). Metastatic bone destruction is driven by a self-reinforcing process coupling osteoclast (OC)-mediated bone degradation to PCa growth, and where cell movement acts to keep these two cooperating cell types in close proximity and to move them across the bone surface. We sought to create a new class of therapeutics that would be highly effective at inhibiting PCa-mediated bone destruction by targeting both OC function and cell motility. Methods: We synthesized new chemical entities, termed Dual Acting Bone Defender agents (DABDs), that couple the small molecule anti-motility agent, KBU2046, with bisphosphonate (bis), through a chemical linker. Assays for in vitro efficacy included: cell migration and invasion, binding to bone mineral, inhibiting osteoclast (OC)-mediated bone destruction, inhibition of Raf1 phosphorylation and inhibition of protein prenylation. In vivo assays included intra-cardiac (IC) injection of human PCa cells into mice, followed by real time monitoring of tumor growth and bone destruction by IVIS and CT imaging, respectively. Findings: We successfully created a novel route of chemical synthesis allowing us to access and probe unique chemical space, providing for single small molecules with bis functional groups linked to a KBU2046 core through a linker moiety. DABDs retain the cellular and molecular characteristics of KBU2046 and bis. Like KBU2046, they inhibit PCa cell motility and phosphorylation of Raf1 on its activation motif. They also inhibit the motility of breast and lung cancer cells. Like bis, they inhibit OC-mediated bone mineral destruction, prenylation of Ras small GTPase proteins, and chemically bind hydroxyapatite. Administered prior to IC injection, DABDs are so effective that they prolong animal survival and inhibit bone destruction in a dose-dependent manner. In mice with established bone metastasis to the femur, after IC injection, DABDs inhibit the growth of tumors. Doses 3,000 fold higher than that required for efficacy had no clinical or critical organ toxicity. Conclusions: DABDs represent a new multifunctional class of therapeutic agents that inhibit PCa-mediated bone destruction and have a high potential for advancing clinical efficacy in PCa patients with bone metastasis. Citation Format: Fangfang Qiao, Ryan Gordon, Abhinandan Pattanayak, Katelyn O’Neill, Nina Chaika, Weining Chen, Rachel Rhatigan, Raymond Bergan. Dual acting bone defender agents inhibit prostate cancer-mediated bone destruction [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 570.

Combining dual-targeted liquid metal nanoparticles with autophagy activation and mild photothermal therapy to treat metastatic breast cancer and inhibit bone destruction.

Although mild photothermal therapy (mild-PTT) avoids treatment bottleneck of the traditional PTT, the application of mild-PTT in deep and internal tumors is severely restricted due to thermal resistance, limited irradiation area and penetration depth. In addition, bone resorption caused by tumor colonization in distal bone tissue exacerbates tumor progression. Here, a strategy was developed for the treatment of bone metastasis and alleviation of bone resorption, which was based on liquid metal (LM) nanoparticle to resist thermal resistance induced by mild-PTT via autophagy activation. Briefly, LM and autophagy activator (Curcumin, Cur) were loaded into zeolitic imidazolate framework-8 (ZIF-8), which was then functionalized with hyaluronic acid/alendronate (CLALN). CLALN exhibited good photothermal performance, drug release ability under acidic environment, specifical recognition and aggregation at bone metastasis sites. CLALN combined with mild-PPT dramatically inhibited tumor progress by inducing the impaired autophagy and reduced the expression of programmed cell death ligand 1 (PD-L1) protein triggered by mild-PTT, resisting thermal resistance and alleviating the immunosuppression. Besides, CLALN combined with mild-PPT effectively alleviated osteolysis compared with only CLALN or mild-PPT. Our experiments demonstrated that this multi-functional LM-based nanoparticle combined with autophagy activation provided a promising therapeutic strategy for bone metastasis treatment. STATEMENT OF SIGNIFICANCE: Due to the limited light penetration, photothermal therapy (PTT) has limited inhibitory effect on tumor cells colonized in the bone. In addition, nonspecific heat diffusion of PTT may accidentally burn normal tissues and damage peripheral blood vessels, which can block the accumulation of drugs in deep tumors. Here, a multifunctional liquid metal based mild-PTT delivery system is designed to inhibit tumor growth and bone resorption by modulating the bone microenvironment and activating autophagy "on demand". It can overcome the treatment bottleneck of traditional PTT and improve the treatment effect of mild-PTT by resisting photothermal resistance and immune suppression. In addition, it also exhibits favorable heat/acid-responsive drug release performance and can specifically target tumor cells at the site of bone metastases.

Traditional Chinese Medicine Rhodiola Sachalinensis Borissova from Baekdu Mountain (RsBBM) for Rheumatoid Arthritis: Therapeutic Effect and Underlying Molecular Mechanisms.

The lack of effective rheumatoid arthritis (RA) therapies is a persistent challenge worldwide, prompting researchers to urgently evaluate traditional Chinese medicines (TCMs) as potential clinical RA treatments. The present investigation was conducted to evaluate the therapeutic effects and potential molecular mechanisms of the active components isolated from TCM Rhodiola sachalinensis Borissova from Baekdu Mountain (RsBBM) using an experimental adjuvant arthritis model induced by injection of rats with Freund’s complete adjuvant. After induction of the adjuvant arthritis rat model, the extract-treated and untreated groups of arthritic rats were evaluated for RsBBM therapeutic effects based on comparisons of ankle circumferences and ELISA-determined blood serum inflammatory factor levels (TNF-α, IL-1β, and PGE2). In addition, the joint health of rats was evaluated via microscopic examination of hematoxylin-eosin-stained synovial tissues. Furthermore, to explore whether NF-κB and RANK/RANKL/OPG signaling pathways participated in observed therapeutic effects from a molecular mechanistic viewpoint, mRNA and protein levels related to the expression of nuclear factor kappa-B (NF-κB), osteoprotegerin (OPG), and receptor activator of nuclear factor kappa-Β ligand (RANKL) were analyzed via quantitative RT-PCR and Western blot analysis, respectively. Treatment of arthritic rats with the extract of RsBBM was shown to reduce ankle swelling, reduce blood serum levels of inflammatory factors, and alleviate arthritis-associated synovial inflammation and joint damage. Moreover, an RsBBM 50% ethanol extract treatment inhibited bone destruction by up-regulating OPG-related mRNA and protein expression and down-regulating RANKL-related mRNA and protein expression, while also reducing inflammation by the down-regulating of the NF-κB pathway activity. The results clearly demonstrated that the extract of RsBBM alleviated adjuvant arthritis-associated joint damage by altering activities of inflammation-associated NF-κB and the RANK/RANKL/OPG signaling pathways. Due to its beneficial effects for alleviating adjuvant arthritis, this RsBBM 50% ethanol extract should be further evaluated as a promising new therapeutic TCM treatment for RA.

CST6 suppresses osteolytic bone disease in multiple myeloma by blocking osteoclast differentiation.

Osteolytic bone disease is a hallmark of multiple myeloma (MM). A significant fraction (~20%) of MM patients do not develop osteolytic lesions (OLs). The molecular basis for the absence of bone disease in MM is not understood. We combined PET-CT and gene expression profiling (GEP) of purified BM CD138+ MM cells from 512 newly diagnosed MM patients to reveal that elevated expression of cystatin M/E (CST6) was significantly associated with the absence of OL in MM. An enzyme-linked immunosorbent assay revealed a strong correlation between CST6 levels in BM serum/plasma and CST6 mRNA expression. Both recombinant CST6 protein and BM serum from patients with high CST6 significantly inhibited the activity of the osteoclast-specific protease cathepsin K and blocked osteoclast differentiation and function. Recombinant CST6 inhibited bone destruction in ex vivo and in vivo myeloma models. Single-cell RNA-Seq showed that CST6 attenuates polarization of monocytes to osteoclast precursors. Furthermore, CST6 protein blocks osteoclast differentiation by suppressing cathepsin-mediated cleavage of NF-κB/p100 and TRAF3 following RANKL stimulation. Secretion by MM cells of CST6, an inhibitor of osteoclast differentiation and function, suppresses osteolytic bone disease in MM and probably other diseases associated with osteoclast-mediated bone loss.

Dual targeted zeolitic imidazolate framework nanoparticles for treating metastatic breast cancer and inhibiting bone destruction

Tumor bone metastasis is still difficult to cure despite the development of various treatment strategies. Drug delivery systems can improve the poor biological distribution of anticancer drugs in tumors. But only a very small number of nanoparticles can cross the physiological barrier to reach the tumor. In addition, the progression of bone metastasis is influenced by tumor cells, osteoclasts and bone matrix. To address these problems, a bone and tumor dual targeted nanocarrier was developed by utilizing NF-κB inhibitor loaded into zeolitic imidazolate framework-8 (ZIF-8) (CZ), which was then coated with hyaluronic acid/alendronate (HA/ALN). The CZ prepared by two-step method had high loading capacity, and the loading efficiency of Cur was to be 47.55 ± 4.03%. HA/ALN functionalization avoided explosive release of reagents and improved the stability of nanoparticles. The dual targeted ZIF-8 nanoparticle (CZ@HA/ALN) had a pH-triggered drug release performance, which effectively inhibited breast cancer cells growth and osteoclastogenesis in vitro. Uptake experiments showed that the conjugation of ALN with HA did not affect targeting ability of HA. Moreover, HA/ALN functionalized nanoparticles were more aggregated at bone metastasis sites than HA functionalized nanoparticles. CZ@HA/ALN could block the PD-1 immune check point, leading to Raw 264.7 cells differentiation into anti-tumor macrophage rather than osteoclast. The antitumor experiments in vivo exhibited that the dual targeted ZIF-8 nanoparticle effectively inhibited bone resorption and tumor progress, thereby improving the bone microenvironment. Therefore, this single but versatile nanoparticle provided a promising therapeutic scheme for bone metastasis treatment.

Combining Dual-Targeted Liquid Metal Nanoparticles with Autophagy Activation and Mild Photothermal Therapy for Treating Metastatic Breast Cancer and Inhibiting Bone Destruction

Combining Dual-Targeted Liquid Metal Nanoparticles with Autophagy Activation and Mild Photothermal Therapy for Treating Metastatic Breast Cancer and Inhibiting Bone Destruction

Evaluation of the protective effects of non-thermal atmospheric plasma on alveolar bone loss in experimental periodontitis.

The inhibition of bone destruction is one of the main goals of periodontitis treatment. The aim of this study was to investigate the protective effects of non-thermal atmospheric plasma (NTAP) on alveolar bone loss radiographically, histomorphometrically, and histologically in experimental periodontitis in rats. A total of twenty-eight rats were randomly divided into three groups: control group (CG) (n = 8), periodontitis group (PG) (n = 10), and NTAP group (NTAPG) (n = 10). In PG and NTAPG, experimental periodontitis was created with ligating. The kINPen 11 plasma jet was applied around the ligatured teeth in NTAPG. The samples from each group were radiographically assessed with microcomputed tomography (micro-CT); then, histological (presence of osteoclasts and inflammatory cells) and immunohistochemical (immunoreactive of OCN and ALP) findings were compared. The results revealed a significant increase in alveolar bone loss in the PG compared with CG and NTAPG (p < 0.05). Inflammation, alveolar resorption, and cement damage were reduced significantly in the group treated with NTAP compared to the PG (p < 0.05). Significantly higher levels of osteoclasts were detected in the PG in comparison with both CG and NTAPG (p < 0.05). The lowest osteocalcin and ALP values were determined in PG, and the differences between PG and both groups were also significant (p < 0.05). Within the limitations of the present study, we can say that NTAP may enhance the bone remodeling process by inhibiting inflammation and preventing alveolar bone destruction. NTAP has clinical potential for accelerating and treating periodontitis with the inflammatory response modulation, osteoblast differentiation, and alveolar bone loss reduction.

Fengshi Qutong capsule ameliorates bone destruction of experimental rheumatoid arthritis by inhibiting osteoclastogenesis

Ethnopharmacological relevanceBone destruction plays a key role in damaging the joint function of rheumatoid arthritis (RA). Fengshi Qutong capsule (FSQTC) consisting of 19 traditional Chinese medicines has been used for treating RA in China for many years. Preliminary studies show that FSQTC has analgesic activity and inhibits synovial angiogenesis of collagen-induced arthritis (CIA), but its role on bone destruction of RA is still unclear. Aim of the studyTo explore the effect of FSQTC on bone destruction of RA and the possible mechanism of osteoclastogenesis in vivo and in vitro. Materials and methodsLC-MS system was used to detect the quality control components of FSQTC. The anti-arthritic effect of FSQTC on CIA rats was evaluated by arthritis score, arthritis incidence and histopathology evaluation of inflamed joints. The effect of treatment with FSQTC on bone destruction of joint tissues was determined with X-ray and micro-CT quantification, and on bone resorption marker CTX-I and formation marker osteocalcin in sera were detected by ELISA. Then, osteoclast differentiation and mature were evaluated by TRAP staining, actin ring immunofluorescence and bone resorption assay both in joints and RANKL-induced RAW264.7 cells. In addition, RANKL, OPG, IL-1β and TNFα in sera were evaluated by ELISA. The molecular mechanisms of the inhibitions were elucidated by analyzing the protein and gene expression of osteoclastic markers CTSK, MMP-9 and β3-Integrin, transcriptional factors c-Fos and NFATc1, as well as phosphorylation of ERK1/2, JNK and P38 in joints and in RANKL-induced RAW264.7 cells using western blot and/or qPCR. ResultsIn this study, 12 major quality control components were identified. Our data showed that FSQTC significantly increased bone mineral density, volume fraction, trabecular thickness, and decreased trabecular separation of inflamed joints both at periarticular and extra-articular locations in CIA rats. FSQTC also diminished the level of CTX-I and simultaneously increased osteocalcin in sera of CIA rats. The effects were accompanied by reductions of osteoclast differentiation, bone resorption, and expression of osteoclastic markers (CTSK, MMP-9 and β3-Integrin) in joints. Interestingly, FSQTC treatment could reduce the protein level of RANKL, increase the expression of OPG, and decrease the ratio of RANKL to OPG in inflamed joints and sera of CIA rats. In addition, FSQTC inhibited the levels of pro-inflammatory cytokines implicated in bone resorption, such as IL-1β and TNFα in sera. When RAW264.7 cells were treated with RANKL, FSQTC inhibited the formation of TRAP + multinucleated cells, actin ring and the bone-resorbing activity in dose-dependent manners. Furthermore, FSQTC reduced the RANKL-induced expression of osteoclastic genes and proteins and transcriptional factors (c-Fos and NFATc1), as well as phosphorylation of mitogen-activated protein kinases (MAPKs). ConclusionFSQTC may inhibit bone destruction of RA by its anti-osteoclastogenic activity both in vivo and in vitro.

Clinical effect and mechanism of moxibustion combined with western medication for rheumatoid arthritis of liver-kidney deficiency

To observe the clinical effect of moxibustion combined with western medication for rheumatoid arthritis (RA) of liver-kidney deficiency, and explore the mechanism of moxibustion for RA. A total of 60 patients with RA of liver-kidney deficiency were randomly divided into an observation group and a control group, 30 cases in each group. In the control group，leflunomide tablets were taken orally, once a day. On the base of the treatment as the control group, moxibustion was applied at Sanyinjiao (SP 6), Shenshu (BL 23), Zusanli (ST 36) and ashi points in the observation group, once every other day, three times a week. Totally 8 weeks were required in both groups. Before and after treatment, the TCM syndrome score, health assessment questionnaire (HAQ) score, 28-joint disease activity score (DAS-28) and serum levels of calcium ion (Ca2+), erythrocyte sedimentation rate (ESR), high-sensitivity C-reactive protein (hs-CRP) and rheumatoid factors (RF) were compared, and the clinicial efficacy was evaluated in the two groups. After treatment, the TCM syndrome scores, HAQ scores and DAS-28 scores were decreased in the two groups (P<0.01), and those in the observation group were lower than the control group (P<0.01). After treatment, the serum levels of Ca2+ were increased (P<0.01), ESR and hs-CRP were decreased in the two groups (P<0.01), and the serum level of RF was decreased in the observation group (P<0.01). The serum level of Ca2+ in the observation group was higher than the control group (P<0.01), ESR and RF were lower than the control group (P<0.01). The total effective rate was 83.3% (25/30) in the observation group，higher than 60.0% (18/30) in the control group (P<0.05). Moxibustion combined with western medication can effectively relieve clinical symptoms, improve quality of life in RA patients, the curative effect is better than simple western medication. And its mechanism may be related to the regulation of serum level of Ca2+ and immune inflammatory response to inhibit bone destruction.

Alendronate-functionalized hypoxia-responsive polymeric micelles for targeted therapy of bone metastatic prostate cancer

Bone metastasis is one of the leading causes of cancer-related death and remains incurable in spite of great efforts. Bone-targeted nanoparticle-based drug carriers can overcome the difficulties in delivering therapeutic agents to metastatic bone and endowing them with a stimuli-responsive feature for controllable drug release can further maximize their therapeutic outcome. In light of hypoxic microenvironment of bone metastasis, we herein reported a bone-targeted and hypoxia-responsive polymeric micelle system for effective treatment of bone metastatic prostate cancer. The micelles were self-assembled from a polyethylene glycol and poly-l-lysine based copolymer using alendronate as a bone-targeted moiety and azobenzene as a hypoxia-responsive linker, showing a high affinity to metastatic bone and a high sensitivity in responding to hypoxia in vitro. In vivo studies further showed that after a selective accumulation in metastatic bone, the micelles could respond to hypoxic bone metastasis for rapid drug release to an effective therapeutic dosage. As a result, the micelles could suppress tumor growth in bone and inhibit bone destruction by inhibiting osteoclast activity and promoting osteoblast activity, achieving an enhanced therapeutic outcome with relieved bone pain and prolonged survival time. Bone-targeted and hypoxia-responsive nanocarriers therefore represent a promising advancement for treating bone metastasis. To our best knowledge, it might be the first example of the application of hypoxia-responsive nanocarriers in treating bone metastasis.

Utility of intraoperative magnetic resonance imaging for giant cell tumor of bone after denosumab treatment: a pilot study.

Giant cell tumor of bone (GCTB) is an intermediate but locally aggressive neoplasm. Current treatment of high-risk GCTB involves administration of denosumab, which inhibits bone destruction and promotes osteosclerosis. However, denosumab monotherapy is not a curative treatment for GCTB and surgical treatment remains required. Denosumab treatment complicates surgery, and the recurrence rate of GCTB is high (20%-30%). To examine the utility of intraoperative magnetic resonance imaging (iMRI) for detection and reduction of residual tumor after denosumab treatment and to investigate the utility of iMRI, which is not yet widely used. We enrolled five patients who received denosumab for a median period of eight months (range 6-12 months). Surgery was performed when the degree of osteosclerosis around the articular surface was deemed appropriate. We performed iMRI using a modified operation table to identify residual tumor after initial curettage and evaluated the rate of detection of residual tumor by iMRI, intraoperative and postoperative complications, exposure time of iMRI, and operation time. Suspected residual tumor tissue was identified in all five cases and was confirmed by histopathology after additional curettage. The rate of detection of residual tumor by iMRI was 100%. Residual tumor was located in sites which were difficult to remove due to osteosclerosis. The iMRI was performed safely and without trouble. During the median follow-up period of 10 months (range 6-24 months), no adverse events or recurrences occurred. Intraoperative MRI could contribute to the reduction of residual tumor tissue and it may prevent recurrence of GCTB after denosumab therapy.

Instant hydrogelation encapsulates drugs onto implants intraoperatively against osteoarticular tuberculosis.

Osteoarticular Tuberculosis (TB) is a challenging issue because of its chronicity and recurrence. Many drug delivery systems (DDSs) have been developed for general chemotherapy. Herein, we take advantage of instant hydrogelation to in situ encapsulate drugs onto implants intraoperatively, optimizing the drug release profile against osteoarticular TB. First-line chemodrugs, i.e. rifampicin (RFP) and isoniazid (INH) are firstly loaded on tricalcium phosphate (TCP). Then, the encapsulating hydrogel is fabricated by dipping in chitosan (CS) and β-glycerophosphate (β-GP) solution and heating at 80 °C for 40 min. The hydrogel encapsulation inhibits explosive drug release initially, but maintains long-term drug release (INH, 158 days; RFP, 53 days) in vitro. Therefore, this technique could inhibit bone destruction and inflammation from TB effectively in vivo, better than our previous ex situ prepared DDSs. The encapsulating technology, i.e. instant hydrogelation of drug-loaded implants, shows potential for regulating the type and ratio of drugs, elastic and viscous modulus of the hydrogel according to the state of illness intraoperatively for optimal drug release.

JTE-952 Suppresses Bone Destruction in Collagen-Induced Arthritis in Mice by Inhibiting Colony Stimulating Factor 1 Receptor

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and structural destruction of the joints. Bone damage occurs in an early stage after onset and osteoclast activation plays a substantial role in its progression. Colony stimulating factor 1 receptor (CSF1R) is a receptor protein tyrosine kinase specifically expressed in monocytic-lineage cells such as macrophages and osteoclasts. Here, we investigated the effect of JTE-952, a novel CSF1R tyrosine kinase inhibitor, on osteoclast formation in vitro and on bone destruction in a mouse model of collagen-induced arthritis. JTE-952 completely inhibited osteoclast differentiation from human monocytes, with an IC50 of 2.8 nmol/L, and reduced osteoclast formation from the synovial cells of RA patients. Detectable levels of colony stimulating factor 1 (CSF1), a ligand of CSF1R, were observed in the synovial tissues of the arthritis model, similar to those observed in the pathology of human RA. JTE-952 significantly suppressed increases in the bone destruction score, the number of tartrate-resistant-acid-phosphatase-positive cells, and the severity of arthritis in the model mice. We also examined the efficacy of JTE-952 combined with methotrexate. This combination therapy more effectively reduced the severity of bone destruction and arthritis than monotherapy with either agent alone. In summary, JTE-952 potently inhibited human osteoclast formation in vitro and suppressed bone destruction in an experimental arthritis model, especially when combined with methotrexate. These results indicate that JTE-952 should strongly inhibit bone destruction and joint inflammation in RA patients and effectively prevent the progression of the structural destruction of joints.

Lupus IgG Induces Synovial Inflammation but Inhibits Bone Erosions in SLE Arthritis

Bone erosion is an important feature of inflammatory arthritis. It remains unknown why lupus arthritis lacks bone erosion and destruction. Our recent published paper presents the interesting discovery that joint deposited lupus IgG triggers synovitis but suppresses osteoclastogenesis which is responsible for bone destruction. In this paper, data show that joint deposited lupus IgG induces synovitis through FcgRI on monocytes/macrophages and blocks RANKL-induced osteoclastogenesis through competing for FcgRI binding with RANKL. This study promotes understanding the pathogenesis of lupus arthritis and provides a novel therapeutic target of FcgRI to inhibit bone destruction in inflammatory arthritis.

Potential Advantages of Bioactive Compounds Extracted From Traditional Chinese Medicine to Inhibit Bone Destructions in Rheumatoid Arthritis.

Bone destruction is an important pathological feature of rheumatoid arthritis (RA), which finally leads to the serious decline of life quality in RA patients. Bone metabolism imbalance is the principal factor of bone destruction in RA, which is manifested by excessive osteoclast-mediated bone resorption and inadequate osteoblast-mediated bone formation. Although current drugs alleviate the process of bone destruction to a certain extent, there are still many deficiencies. Recent studies have shown that traditional Chinese medicine (TCM) could effectively suppress bone destruction of RA. Some bioactive compounds from TCM have shown good effect on inhibiting osteoclast differentiation and promoting osteoblast proliferation. This article reviews the research progress of bioactive compounds exacted from TCM in inhibiting bone destruction of RA, so as to provide references for further clinical and scientific research.

Thermogel Delivers Oxaliplatin and Alendronate in situ for Synergistic Osteosarcoma Therapy.

The therapeutic effect of osteosarcoma (OS) has not made extraordinary progress in the past few decades. Oxaliplatin (OXA) is a widely used clinical anti-tumor drug. Recent studies have shown that OXA can trigger anti-tumor immunity by inducing immunogenic death (ICD). Alendronate (ALN) has been used to threaten the skeletal system tumors because of the unique bone affinity and the ability to inhibit bone destruction. In this study, we co-loaded OXA and ALN on mPEG45–PLV19 thermo-sensitive hydrogel to perform in situ treatment on the mouse OS model. Slowly released OXA can induce immunogenic death of tumor cells. At the same time, thermo-sensitive hydrogels can induce the accumulation of cytotoxic T lymphocytes. Besides, ALN could synergistically diminish tumors and prevent bone destruction. This system could synergistically inhibit the progression of OS and lung metastasis and has no toxicity to various organs throughout the body.

Bone marrow mesenchymal stem cells improve bone erosion in collagen-induced arthritis by inhibiting osteoclasia-related factors and differentiating into chondrocytes

BackgroundRheumatoid arthritis (RA) is characterized by joint inflammation and damage to the cartilage and bone in collagen-induced arthritis (CIA). Mesenchymal stem cells (MSCs) can improve articular symptoms and reduce bone erosion in CIA rats; however, the underlying mechanism remains unknown. This study aimed to investigate the mechanism underlying MSC-induced improvement of bone destruction in CIA.MethodsWistar rats were divided into a normal group, CIA control group, MTX intervention group, and BMSC intervention group, each comprising 8 rats. Serum RANKL, OPG, and CXCL10 levels of all groups were determined via flow cytometry after 42 days of interventions. RANKL, OPG, TRAF6, CXCL10, and CXCR3 were detected on the synovial membrane via immunohistochemistry, and their relative mRNA levels were determined via RT-PCR analysis. BMSCs were labeled with GFP and administered to CIA rats via the tail vein. At different time points, the distribution of implanted GFP-MSCs in synovial tissues was observed using a fluorescence microscope, and the potential of GFP-MSCs to differentiate into chondrocytes was assessed via immunofluorescence analysis.ResultsBMSC transplantation improved joint inflammation and inhibited bone destruction in CIA rats. BMSCs inhibited the expression of serum CXCL10 and CXCL10 and CXCR3 expression at the synovial membrane. Moreover, protein and mRNA expression analyses revealed that BMSCs potentially regulated RANKL/OPG expression levels in the serum and synovial tissue. Upon implantation into CIA rats, GFP-MSCs were traced in the joints. GFP-positive cells were observed in the cartilage tissue from day 11 and until 42 days after transplantation. Anti-type II collagen/GFP double-positive cells were observed in the articular cartilage (especially damaged cartilage) upon immunofluorescence staining of anti-type II collagen.ConclusionsBMSCs improve bone destruction in CIA by inhibiting the CXCL10/CXCR3 chemotactic axis, regulating the RANKL/OPG ratio, and directly differentiating into chondrocytes.

Glyburide inhibits the bone resorption induced by traumatic occlusion in rats.

To examine whether glyburide inhibits bone destruction caused by traumatic occlusion in a rat occlusal trauma model. Excessive mechanical stress, such as traumatic occlusion, induces expression of IL-1β and may be involved in bone resorption. NLRP3 inflammasomes have been linked to IL-1β expression, but it is currently unclear whether glyburide, the inhibiter of NLRP3 inflammasome, suppresses occlusal trauma in rats. Male SD rats aged 7weeks were used. In the trauma group, the occlusal surface of the maxillary first right molar was raised by attaching a metal wire to apply occlusal trauma to the mandibular first right molar. In the trauma+glyburide group, the NLRP3 inhibitor glyburide was administered orally every 24hours from 1day before induction of occlusal trauma. Rats were euthanized after 5 or 10days, and the maxillary first molars were harvested with the adjacent tissues for histopathological investigation. Immunohistochemical expression of IL-1β, NLRP3, and RANKL was also assessed. On day 5, bone resorption was significantly greater in the trauma group compared with the control group or the trauma+glyburide group, and there were significantly higher numbers of osteoclasts and cells positive for IL-1β, NLRP3, and RANKL in the trauma group. In this study, glyburide inhibits bone resorption by traumatic occlusion in rats. It suggests that the NLRP3/IL-1β pathway might be associated with bone resorption induced by traumatic occlusion.