MRI-based Zero Echo Time and Black Bone Pseudo-CT Compared with Whole-Body CT to Detect Osteolytic Lesions in Multiple Myeloma.

Background MRI is highly sensitive for assessing bone marrow involvement in multiple myeloma (MM) but does not enable detection of osteolysis. Purpose To assess the diagnostic accuracy, repeatability, and reproducibility of pseudo-CT MRI sequences (zero echo time [ZTE], gradient-echo black bone [BB]) in detecting osteolytic lesions in MM using whole-body CT as the reference standard. Materials and Methods In this prospective study, consecutive patients were enrolled in our academic hospital between June 2021 and December 2022. Inclusion criteria were newly diagnosed MM, monoclonal gammopathy of undetermined significance at high risk for MM, or suspicion of progressive MM. Participants underwent ZTE and BB sequences covering the lumbar spine, pelvis, and proximal femurs as part of 3-T whole-body MRI examinations, as well as clinically indicated fluorine 18 fluorodeoxyglucose PET/CT examination within 1 month that included optimized whole-body CT. Ten bone regions and two scores (categorical score = presence/absence of osteolytic lesion; semiquantitative score = osteolytic lesion count) were assessed by three radiologists (two experienced and one unfamiliar with pseudo-CT reading) on the ZTE, BB, and whole-body CT images. The accuracy, repeatability, and reproducibility of categorical scores (according to Gwet agreement coefficients AC1 and AC2) and differences in semiquantitative scores were assessed at the per-sequence, per-region, and per-patient levels. Results A total of 47 participants (mean age, 67 years ± 11 [SD]; 27 male) were included. In experienced readers, BB and ZTE had the same high accuracy (98%) in the per-patient analysis, while BB accuracy ranged 83%-100% and ZTE accuracy ranged 74%-94% in the per-region analysis. An increase of false-negative (FN) findings in the spine ranging from +17% up to +23%, according to the lumbar vertebra, was observed using ZTE (P < .013). Regardless of the region (except coxal bones), differences in the BB score minus the ZTE score were positively skewed (P < .021). Regardless of the sequence or region, repeatability was very good (AC1 ≥0.87 for all), while reproducibility was at least good (AC2 ≥0.63 for all). Conclusion Both MRI-based ZTE and BB pseudo-CT sequences of the lumbar spine, pelvis, and femurs demonstrated high diagnostic accuracy in detecting osteolytic lesions in MM. Compared with BB, the ZTE sequence yielded more FN findings in the spine. ClinicalTrials.gov Identifier: NCT05381077 Published under a CC BY 4.0 license. Supplemental material is available for this article.

Fixing Cho Type IIC Distal Clavicle Fractures with Hook Plates Leads to a High Incidence of Subacromial Osteolysis: A Retrospective Study and Literature Review.

Background: This retrospective study investigates the complications, particularly subacromial osteolysis (SAO), associated with hook plate (HP) fixation, in the treatment of unstable distal clavicle fractures characterized by complete coracoclavicular (CC) ligament rupture. The decision-making process for employing HP in fractures of this nature, such as Neer types IIB and V and Cho classification IIC, involves considerations of distal fragment size and displacement. While HP offers advantages in clinical practice, it is not without complications, with SAO being a notable concern. Factors such as non-anatomic hook tip placement and fracture classification may influence the risk of SAO. Methods: The study comprises a retrospective analysis of unstable distal clavicle fractures treated with HP at our institution from 2019 to 2022. Exclusions include non-displaced fractures, those treated with other locking plates, and pathologic fractures. A total of 91 patients with displaced distal clavicle fractures underwent open reduction and internal fixation with HP. Cho classification was employed to differentiate cases with CC ligament rupture. Patient demographics, classifications, postoperative radiographs, distal fragment size, plate position, timing of implant removal, and complications, including SAO, were recorded. Results: Among the 91 patients, 32 were classified as Cho IIB, 43 as Cho IIC, and 16 as Cho IID. Ninety-one percent exhibited solid union before implant removal. The prevalence of SAO was 43.8%, 76.7%, and 62.5% in Cho IIB, IIC, and IID, respectively. Univariate analysis revealed a significant difference only in Cho classification (p = 0.014). Binary logistic regression identified Cho classification type IIC as the sole risk factor for SAO (p = 0.021; odds ratio, 4.48; 95% confidence interval, 1.56-12.87). Conclusions: Cho type IIC fractures, characterized by CC ligament deficiency causing horizontal instability, demonstrated the highest SAO rate. In contrast, Neer type IIB fractures retained the trapezoid ligament, and Neer type V fractures had intact CC ligaments, resulting in lower SAO rates. Biomechanically, combining HPs with CC ligament reconstruction provided better structural stability than using HPs alone in treating Cho type IIC fractures.

Matrix-bound nanovesicles alleviate particulate-induced periprosthetic osteolysis.

Aseptic loosening of orthopedic implants is an inflammatory disease characterized by immune cell activation, chronic inflammation, and destruction of periprosthetic bone, and is one of the leading reasons for prosthetic failure, affecting 12% of total joint arthroplasty patients. Matrix-bound nanovesicles (MBVs) are a subclass of extracellular vesicle recently shown to mitigate inflammation in preclinical models of rheumatoid arthritis and influenza-mediated "cytokine storm." The molecular mechanism of these anti-inflammatory properties is only partially understood. The objective of the present study was to investigate the effects of MBV on RANKL-induced osteoclast formation in vitro and particulate-induced osteolysis in vivo. Results showed that MBV attenuated osteoclast differentiation and activity by suppressing the NF-κB signaling pathway and downstream NFATc1, DC-STAMP, c-Src, and cathepsin K expression. In vivo, local administration of MBV attenuated ultrahigh molecular weight polyethylene particle-induced osteolysis, bone reconstruction, and periosteal inflammation. The results suggest that MBV may be a therapeutic option for preventing periprosthetic loosening.

Insight into prostate cancer osteolytic metastasis by RelB coordination of IL-8 and S100A4.

BACKGROUND: Although RANK-LRANK interaction is essential for osteoclastogenesis, the mechanisms by which cancer cells invade bone tissues and initiate osteolytic metastasis remain unclear. Here, we show that the hyperactivation of RelB fosters prostate cancer (PCa) osteolytic metastasis by coordinating interleukin-8 (IL-8) and calcium-binging protein A4 (S100A4). METHODS: The factors promoting PCa bone metastasis were investigated in sera from PCa patients and tumour tissues derived from nude mice using immunohistochemical analysis and enzyme-linked immunosorbent assays (ELISA). Cell mobility and mineralization were quantified using BioStation CT and Osteolmage assay. The relative cistrome was investigated in advanced PCa cells by standard transcriptional analyses, including the luciferase reporter response, site-directed mutagenesis, and chromatin immunoprecipitation (ChIP) assay. PCa cell-initiated tumour formation, expansion, and bone metastasis were validated in mice using multiple approaches, including orthotopic, intraskeletal, and caudal arterial implantation models. RESULTS: IL-8 and S100A4 correlated with patient Gleason scores and bone metastasis. RelB upregulated IL-8, facilitating androgen receptor (AR)-independent growth. RelB-Sp1 interaction enhanced epithelial-mesenchymal transition (EMT) by activating Snail and Twist. RelB-NFAT1c super-enhancer upregulated S100A4 in the organization of the cytoskeleton and bone metastasis. The RelB-IL-8-S100A4 signalling axis was confirmed to promote osteolytic metastasis in nude mice. CONCLUSION: RelB-IL-8 reciprocally promoted EMT by activating inflammatory signalling and inactivating AR signalling. IL-8 is essential for provoking PCa metastasis but insufficient to drive bone metastasis. IL-8-S100A4 cooperation was necessary for metastatic cells to target the bone. HIGHLIGHTS: RelB activates inflammatory signalling by upregulating IL-8 and suppressing AR. RelB upregulates S100A4 by cooperating with NFATC1. IL-8 boosts EMT by activating Snail 1 and Twist 1, and S100A4 exacerbates osteolytic metastasis via calcium consumption. RelB harnesses IL-8 and S100A4 to drive PCa osteolytic metastasis.

[Long-term computed tomographic osteolytic analysis of highly cross-linked polyethylene prosthesis after total hip arthroplasty].

Objective: To analyze the occurrence of osteolysis in total hip arthroplasty (THA) with highly cross-linked polyethylene prosthesis during a follow-up of more than 15 years. Methods: The clinical data of 84 patients (105 hips) treated with THA in the Affiliated Hospital of Kanazawa Medical University in Japan between June 2000 and April 2004 and met the selection criteria was retrospectively analyzed. There were 7 males and 77 females, aged from 41 to 75 years, with an average of 56.4 years. There were 94 hips with secondary hip osteoarthritis, 4 hips after pelvic osteotomy, 2 hips with primary hip osteoarthritis, 2 hips with traumatic hip osteoarthritis, 2 hips with osteonecrosis of the femoral head, and 1 hip with rheumatoid arthritis. According to Crowe classification, there were 79 hips of type Ⅰ, 19 hips of type Ⅱ, 6 hips of type Ⅲ, and 1 hip of type Ⅳ. The highly cross-linked polyethylene acetabular liner combined with a 26 mm zirconia femoral head were used in all patients. X-ray films were taken after operation to analyze the radiation transmission and osteolysis around the acetabular prosthesis. The vertical distance (the distance between the teardrop line at the lower edge of the pelvis and the perpendicular line of the hip rotation center), the horizontal distance (the horizontal distance between the hip rotation center and the interteardrop line and the vertical line at the lower edge of the teardrop), and the acetabular cup anteversion angle were measured at last follow-up. The acetabular and femoral osteolysis was analyzed by CT scan and three-dimensional multiplanar reconstruction (3D-MPR). Combined with X-ray film and CT results, osteolysis was evaluated according to the Narkbunnam score. Results: Deep vein thrombosis of lower limbs occurred in 2 cases. All patients were followed up 15-18 years, with an average of 15.9 years. One hip dislocation and 1 periprosthetic fracture occurred postoperatively, and no acetabular loosening or prosthetic lining ruptures occurred. Except for 1 patient who had a radiolucent line in the acetabulum after operation, the other 83 patients did not show any radiolucent line in the acetabulum or the femur. None of the patients underwent hip revision. X-ray films at last follow-up showed an acetabular cup anteversion angle of -10°-39°, with an average of 22°; a vertical distance of 3.5-47.1 mm, with an average of 24.6 mm; and a horizontal distance of 22.6-48.1 mm, with an average of 31.7 mm. There was no acetabular or femoral osteolysis in all patients on X-ray films and CT 3D-MPR images at last follow-up, and the Narkbunnam score was 0 in any region. Conclusion: Highly cross-linked polyethylene prosthesis does not increase the risk of long-term complications such as osteolysis after THA.

Albiflorin inhibits osteoclastogenesis and titanium particles-induced osteolysis via inhibition of ROS accumulation and the PI3K/AKT signaling pathway.

Periprosthetic osteolysis (PPO), caused by wear particles, is a significant complication of total joint replacement, leading to prosthesis failure. Previous research has highlighted the crucial role of osteoclast-induced bone destruction in PPO progression. Albiflorin (AF), a monoterpene glycoside from Paeonia lactiflora, is a key active ingredient known for its antioxidant and anti-inflammatory properties. Although AF has shown promise in treating various conditions, its impact on osteoclasts and PPO remains unexplored. Our study revealed that AF could effectively inhibit osteoclast differentiation to reduce overactivated bone resorption and effectively inhibit the accumulation of reactive oxygen species (ROS) induced by wear particles. In vitro experiments also confirmed that AF could effectively inhibit the PI3K/AKT signaling pathway and inhibit inflammation to regulate osteoclast generation. Studies in animal models have also verified the antioxidant and anti-inflammatory properties of AF. In summary, the above studies indicate that AF inhibits osteoclastogenesis via inhibiting ROS accumulation and the PI3K/AKT signaling pathway, which may be a potential therapeutic method for PPO.

lncRNA H19 plays a role in multiple myeloma via interacting with hnRNPA2B1 to stabilize BET proteins by targeting osteoclasts and osteoblasts.

BACKGROUND: Multiple myeloma (MM), characterized with bone marrow microenvironment disorder, accounts for about 20% of hematological cancer deaths globally. Tissue extracellular communication, especially extracellular vesicles, has been defined as important mediator among cell-to-cell cross-talk. Our previous study revealed an elevated level of H19 in MM, whereas, its role in MM exosomes in the development of osteolysis remains largely unknown. METHOD: MM exosomes referring to 5TGM1 cells were isolated and characterized using transmission electron microscopy (TEM), nanoparticle tracking and western blot analysis. The biological effects of blocking H19 were examined on osteolysis in vivo of C57Bl6/KalwRij mice, as well as on the osteoclast differentiation in vitro of RAW264.7 cells, by the application of TRAP, either with osteogenic differentiation in vitro of bone marrow mesenchymal stem cells (BMSCs), by the detection of alkaline phosphatase (ALP), alizarin red dye staining (ARS). The targeted relationships among H19/hnRNPA2B1/BET proteins were validated through RNA immunoprecipitation (RIP) and RNA pull-down assays. RESULTS: 5TGM1 cells derived-exosomes lacking H19 dramatically blocked osteolysis and boosted osteogeneis in C57Bl6/KalwRij mice, either with osteoclastic differentiation of RAW264.7 cells and osteogenic differentiation of BMSCs, thereby enhancing their resorptive activity. Physically, H19 interacted with hnRNPA2B1 by preferentially adhering to it and enhancing its nuclear-cytoplasmic translocation. Further mechanistic research validated that H19 promoted the stabilization of BET proteins through hnRNA2B1 to be involved in osteoclast differentiation for contributing to MM progression. CONCLUSION: Altogether, our findings suggest that H19, serving as an essential role for exosomes in the bone marrow environment, might be a viable diagnostic and therapeutic target for MM therapy.

Corydaline attenuates osteolysis in rheumatoid arthritis via mitigating reactive oxygen species production and suppressing calcineurin-Nfatc1 signaling.

AIM OF THE STUDY: Osteolysis in Rheumatoid arthritis (RA) is principally provoked by osteoclast hyperactivity. This study aims to employ Corydaline (Cory), a plant extract, as an osteoclast inhibitor in treating RA-inflicted osteolysis while unveiling the corresponding mechanism. MATERIALS AND METHODS: Osteoclasts were derived from mouse bone marrow-derived monocytes (BMMs) stimulated with M-CSF and RANKL. Subsequently, utilizing network pharmacology, we performed a thorough analysis of Cory's molecular structure and discerned its preliminary therapeutic potential. Subsequently, LPS was used to simulate and establish an in vitro model of RA, and the biological effect of Cory on osteoclast behaviors was evaluated through various staining methods, RT-qPCR, and Western blot. In addition, a collagen-induced arthritis (CIA) mouse model was developed to evaluate the therapeutic effects of Cory in vivo. RESULTS: The results from network pharmacology indicated a significant correlation between Cory, oxidative stress, and calcium signaling. Subsequent in vitro experiments demonstrated Cory's capacity to inhibit the formation and function of osteoclast under inflammatory stimuli, thereby protecting against abnormal bone resorption. This effect is achieved by activating the Nrf2 signaling pathway, mitigating the generation of reactive oxygen species (ROS), and modulating the calcineurin-Nfatc1 signaling. Furthermore, this therapeutic effect of Cory on RA-associated osteolysis was proved in CIA mice models. CONCLUSIONS: Cory demonstrates the potential to activate the Nrf2 signaling pathway, effectively countering oxidative stress, and simultaneously inhibit the calcineurin-Nfatc1 signaling pathway to regulate the terminals of calcium signaling. These dual effects collectively reduce osteoclast activity, ultimately contributing to a therapeutic role in RA osteolysis. Therefore, our study presents Cory as a novel pharmaceutical candidate for the prevention and treatment of RA.

The Role of Receptor Activator of Nuclear Factor-κB Ligand/Osteoprotegerin Ratio in Synovial Fluid as a Potential Marker for Periprosthetic Osteolysis Following Total Ankle Arthroplasty.

Background: Periprosthetic osteolysis is a prevalent complication following total ankle arthroplasty (TAA), implicating various cytokines in osteoclastogenesis as pivotal in this process. This study aimed to evaluate the relationship between osteolysis and the concentrations of osteoclastogenesis-related cytokines in synovial fluid and investigate its clinical value following TAA. Methods: Synovial fluid samples from 23 ankles that underwent revision surgery for osteolysis following TAA were analyzed as the osteolysis group. As a control group, we included synovial fluid samples obtained from 23 ankles during primary TAA for osteoarthritis. The receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) ratio in these samples was quantified using sandwich enzyme-linked immunosorbent assay techniques, and a bead-based multiplex immunoassay facilitated the detection of specific osteoclastogenesis-related cytokines. Results: RANKL levels averaged 487.9 pg/mL in 14 of 23 patients in the osteolysis group, with no detection in the control group's synovial fluid. Conversely, a significant reduction in OPG levels was observed in the osteolysis group (p = 0.002), resulting in a markedly higher mean RANKL/OPG ratio (0.23) relative to controls (p = 0.020). Moreover, the osteolysis group had increased concentrations of various osteoclastogenesis-related cytokines (tumor necrosis factor-α, interleukin [IL]-1ß, IL-6, IL-8, IP-10, and monocyte chemotactic protein-1) in the synovial fluid relative to the control group. Conclusions: Our results demonstrated that periprosthetic osteolysis was associated with osteoclastogenesis activation through an elevated RANKL/OPG ratio following TAA. We assume that RANKL and other osteoclastogenesis-related cytokines in the synovial fluid have clinical value as a potential marker for the development and progression of osteolysis following TAA.

Oxysophocarpine attenuates inflammatory osteolysis by modulating the NF-κb pathway and the reactive oxygen species-related Nrf2 signaling pathway.

BACKGROUND AND AIM: Inflammatory diseases often result in bone loss due to persistent inflammation, which activates osteoclasts and increases bone resorption. Oxysophocarpine (OSC), a bioalkaloid extracted from the roots of Sophora japonica and other leguminous plants, has neuroprotective and anti-tumor properties. However, it is still uncertain whether OSC can effectively inhibit the differentiation of osteoclasts and bone resorption. Therefore, this study explored the potential role of OSC in osteoclast formation and inflammatory osteolysis and its underlying mechanisms. EXPERIMENTAL PROCEDURE: This study involved inducing primary mouse bone marrow macrophages (BMMs) into osteoclasts using macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL) and examined the effects of OSC on osteoclast (OC) differentiation, function, and intracellular reactive oxygen species (ROS) production. The impact of OSC on the expression of osteoclast-specific genes and inflammation-related factors was assessed using real-time quantitative PCR. Additionally, changes in oxidative stress-related factors, NF-κB, and MAPK signaling pathways were examined using western blotting. Finally, this study investigated the influence of OSC on a mouse cranial bone resorption model induced by titanium (Ti) particles in vivo. RESULTS: OSC inhibited OC differentiation and resorption and reduces intracellular ROS levels. Moreover, OSC suppressed IL-1ß, TNF-α, IL-6, and osteoclast-specific gene transcription while increasing Nrf2 and HO-1 protein expression. Furthermore, OSC inhibited the expression and autoregulation of the NFATc1 gene, ultimately leading to a reduction in Ti particle-induced bone resorption in mice. CONCLUSION: OSC could be regarded as an innovative medication for the treatment of osteoclast-associated inflammatory osteolytic diseases.

Lymphotoxin-ß promotes breast cancer bone metastasis colonization and osteolytic outgrowth.

Bone metastasis is a lethal consequence of breast cancer. Here we used single-cell transcriptomics to investigate the molecular mechanisms underlying bone metastasis colonization-the rate-limiting step in the metastatic cascade. We identified that lymphotoxin-ß (LTß) is highly expressed in tumour cells within the bone microenvironment and this expression is associated with poor bone metastasis-free survival. LTß promotes tumour cell colonization and outgrowth in multiple breast cancer models. Mechanistically, tumour-derived LTß activates osteoblasts through nuclear factor-κB2 signalling to secrete CCL2/5, which facilitates tumour cell adhesion to osteoblasts and accelerates osteoclastogenesis, leading to bone metastasis progression. Blocking LTß signalling with a decoy receptor significantly suppressed bone metastasis in vivo, whereas clinical sample analysis revealed significantly higher LTß expression in bone metastases than in primary tumours. Our findings highlight LTß as a bone niche-induced factor that promotes tumour cell colonization and osteolytic outgrowth and underscore its potential as a therapeutic target for patients with bone metastatic disease.

The HOXC10/NOD1/ERK axis drives osteolytic bone metastasis of pan-KRAS-mutant lung cancer.

While KRAS mutation is the leading cause of low survival rates in lung cancer bone metastasis patients, effective treatments are still lacking. Here, we identified homeobox C10 (HOXC10) as a lynchpin in pan-KRAS-mutant lung cancer bone metastasis. Through RNA-seq approach and patient tissue studies, we demonstrated that HOXC10 expression was dramatically increased. Genetic depletion of HOXC10 preferentially impeded cell proliferation and migration in vitro. The bioluminescence imaging and micro-CT results demonstrated that inhibition of HOXC10 significantly reduced bone metastasis of KRAS-mutant lung cancer in vivo. Mechanistically, the transcription factor HOXC10 activated NOD1/ERK signaling pathway to reprogram epithelial-mesenchymal transition (EMT) and bone microenvironment by activating the NOD1 promoter. Strikingly, inhibition of HOXC10 in combination with STAT3 inhibitor was effective against KRAS-mutant lung cancer bone metastasis by triggering ferroptosis. Taken together, these findings reveal that HOXC10 effectively alleviates pan-KRAS-mutant lung cancer with bone metastasis in the NOD1/ERK axis-dependent manner, and support further development of an effective combinatorial strategy for this kind of disease.

An Incidental Detection of Breast Cancer Osteolytic Bone Metastasis Using a 99m Tc-TRODAT-1 SPECT Scan.

ABSTRACT: This report presents a case of suspected Parkinson disease in a 76-year-old woman with a history of slurred speech, general weakness, unstable gait, and bradykinesia for months. A 99m Tc-TRODAT-1 SPECT scan revealed a symmetrically decreased bilateral nigrostriatal system, including bilateral putamen and caudate nuclei. The scintigraphic findings may reflect normal aging or atypical parkinsonism. The bilateral frontal bones and left temporal bone exhibited increased uptake of 99m Tc-TRODAT-1, and previous 99m Tc-MDP bone scan and CT images were reviewed. Osteolytic lesions at the corresponding site indicated bone metastasis from breast cancer.

Trifolirhizin reduces osteoclast formation and prevents inflammatory osteolysis by inhibiting RANKL-induced activation of NF-κB and MAPK signaling pathways and ROS.

Inflammatory osteolysis is often caused by the excessive activation of osteoclasts stimulated by bacterial products such as lipopolysaccharide. The natural flavonoid trifolirhizin (TRI) has anti-inflammatory properties; however, its function in inflammatory bone lysis remains unclear. This study aimed to elucidate the potential regulatory mechanisms of TRI in osteoclasts.Tartrate-resistant acid phosphatase (TRAP) staining, acid secretion assays, podosomal actin belt fluorescence staining, and bone resorption assays were used to investigate the effects of TRI on osteoclast differentiation and bone resorption. A reactive oxygen species (ROS) measurement kit was used to detect the effect of TRI on ROS levels in osteoclasts. The effects of TRI on genes and signaling pathways related to osteoclast differentiation were determined by quantitative polymerase chain reaction (qPCR) and western blotting. A mouse model of lipopolysaccharide-mediated inflammatory osteolysis was established, and the effects of TRI treatment on bone mass were observed using micro-CT and histological examination. Mechanistically, TRI reduced ROS production by inhibiting receptor activator of nuclear factor-κB ligand (RANKL)-induced activation of the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, and by upregulating the expression levels of the anti-ROS enzymes heme oxygenase-1 (HO-1) and catalase (CAT), which contributed to the degradation of ROS, ultimately leading to a decrease in osteoclastogenesis. TRI inhibited osteoclast formation and ameliorated lipopolysaccharide (LPS)-mediated inflammatory osteolysis. Thus, TRI may be a candidate agent for anti-inflammatory osteolysis.

LMK-235 suppresses osteoclastogenesis and promotes osteoblastogenesis by inhibiting HDAC4.

Osteoblasts and osteoclasts play an important role in maintaining the structural integrity of bone tissue, in which osteoclasts degrade bone structure and osteoblasts restore bone tissue. The imbalance of osteoblast and osteoclast function can lead to many bone-related diseases, such as osteoporosis and inflammatory osteolysis. The drug that can both promote bone formation and inhibit bone loss will be able to treat those diseases. In this study, it was found that LMK-235, an selective HDAC4/5 inhibitor, inhibited the differentiation and maturation of osteoclasts by regulating NF-κB and p-Smad2/3 signaling pathways via inhibition of HDAC4. At the same time, we found that LMK-235 promoted osteoblast mineralization by upregulating Runx2 expression via inhibition of HDAC4. In vivo, LMK-235 was able to alleviate lipopolysaccharide (LPS)-induced calvarial osteolysis and promote the repair of bone defects. Taken together, LMK-235 suppresses osteoclast differentiation and promotes osteoblast formation by inhibiting HDAC4. This may provide a valuable treatment for bone diseases caused by abnormal osteoclast bone resorption and osteoblast bone regeneration.

[28-year-old male patient with headaches on the left side and facial pain]. / 28-jähriger Patient mit in den Kiefer ausstrahlenden ­Kopfschmerzen temporal links.

INTRODUCTION: A 28-year-old male suffers for two weeks from new-onset very severe headache located on his left temple radiating to his jaw. He also complains about left sided retroorbital pain and chewing aggravated symptoms. In addition, nausea and emesis in the mornings during the past six months were reported. Clinical examination revealed tender swelling over the left temple, but laboratory results showed no signs of inflammation, normal electrolytes, kidney and liver values. A CT-scan revealed a circumscriptive osteolytic lesion in the left os temporale.

Preventing periprosthetic osteolysis in aging populations through lymphatic activation and stem cell-associated secretory phenotype inhibition.

With increases in life expectancy, the number of patients requiring joint replacement therapy and experiencing periprosthetic osteolysis, the most common complication leading to implant failure, is growing or underestimated. In this study, we found that osteolysis progression and osteoclast differentiation in the surface of the skull bone of adult mice were accompanied by significant expansion of lymphatic vessels within bones. Using recombinant VEGF-C protein to activate VEGFR3 and promote proliferation of lymphatic vessels in bone, we counteracted excessive differentiation of osteoclasts and osteolysis caused by titanium alloy particles or inflammatory cytokines LPS/TNF-α. However, this effect was not observed in aged mice because adipogenically differentiated mesenchymal stem cells (MSCs) inhibited the response of lymphatic endothelial cells to agonist proteins. The addition of the JAK inhibitor ruxolitinib restored the response of lymphatic vessels to external stimuli in aged mice to protect against osteolysis progression. These findings suggest that inhibiting SASP secretion by adipogenically differentiated MSCs while activating lymphatic vessels in bone offers a new method to prevent periprosthetic osteolysis during joint replacement follow-up.

Ophthalmologic Symptoms in a Patient With Autosomal Dominant Multicentric Carpotarsal Osteolysis.

PURPOSE: The purpose of this case report was to provide a detailed description of the ocular manifestations, in a patient with multicentric carpotarsal osteolysis (MCTO), with particular emphasis on bilateral corneal opacities. METHODS: A 43-year-old woman with a history of MCTO was followed with visual acuity assessment and slit-lamp examination at the Department of Ophthalmology in the University Hospitals of Leuven. RESULTS: The patient was found to have bilateral subepithelial haze, along with anterior stromal corneal opacities, and small central lens opacities upon examination. There was a slight corneal thickening. A progression of the corneal opacities was observed, without a further drop in visual acuity. CONCLUSIONS: This case report shows a rare association between MCTO and corneal opacities in adulthood. Interdisciplinary care involving an ophthalmologist is beneficiary for patients with MCTO.

Cutibacterium acnes invades submicron osteocyte lacuno-canalicular networks following implant-associated osteomyelitis.

Cutibacterium acnes, part of normal skin flora, is increasingly recognized as an opportunistic pathogen capable of causing chronic prosthetic joint infections (PJI) associated with total hip and knee arthroplasty. However, there is a paucity of literature examining the pathogenesis of C. acnes during PJI. To study this, we developed an implant-associated osteomyelitis murine model in which 8-10-week-old C57BL6 mice were subjected to transtibial implantation of titanium or stainless-steel L-shaped pins contaminated with C. acnes. Postsurgery, mice were killed on Days 14 and 28 for terminal assessments of (1) bacterial load in bone, implant, and internal organs (heart, spleen, kidney, and liver), (2) bone osteolysis (micro-CT), (3) abscess formation (histology), and (4) systematic electron microscopy (EM). In vitro scanning EM (SEM) confirmed that C. acnes can form biofilms on stainless-steel and titanium implants. In mice, C. acnes could persist for 28 days in the tibia. Also, we observed C. acnes dissemination to internal organs. C. acnes chronic osteomyelitis revealed markedly reduced bone osteolysis and abscess formation compared to Staphylococcus aureus infections. Importantly, transmission EM (TEM) investigation revealed the presence of C. acnes within canaliculi, demonstrating that C. acnes can invade the osteocyte lacuno-canalicular networks (OLCN) within bone. Our preliminary pilot study, for the first time, revealed that the OLCN in bone can be a reservoir for C. acnes and potentially provides a novel mechanism of why C. acnes chronic implant-associated bone infections are difficult to treat.