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.

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.

BACKGROUND: 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.
UNASSIGNED: 28-jähriger Patient mit in den Kiefer ausstrahlenden ­Kopfschmerzen temporal links.
UNASSIGNED: Ein 28-jähriger Mann klagt seit zwei Wochen über neu aufgetretene akute, pochende Kopfschmerzen temporal links. Die Schmerzstärke beträgt VAS 8/10 mit Ausstrahlung in den Kiefer. Schmerzauslöser sind Kauen und Druck auf die Schläfe. Zusätzlich gibt der Patient drückende Schmerzen retroorbital links an. Als Begleitsymptom besteht seit sechs Monaten Nüchternerbrechen. Die klinische Untersuchung ist bis auf eine druckdolente Schwellung der linken Schläfe bland. Die Labordiagnostik ist unauffällig. In der CT des Neurokraniums ist der Nachweis einer osteolytischen Läsion im Os temporal links sichtbar. Schlüsselwörter: Langerhans-Zell-Histiozytose, Kopfschmerzen, LZH, ZNS, Tumor.

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.

To alleviate bone loss, most current drugs target osteoclasts. Saikosaponin A (Ssa), a triterpene saponin derived from Bupleurum falcatum (also known as Radix bupleuri), has immunoregulatory, neuromodulatory, antiviral, anticancer, anti-convulsant, anti-inflammatory, and anti-proliferative effects. Recently, modulation of bone homeostasis was shown to involve ferroptosis. Herein, we aimed to determine Ssa\'s inhibitory effects on osteoclastogenesis and differentiation, whether ferroptosis is involved, and the underlying mechanisms. Tartrate-resistant acid phosphatase (TRAP) staining, F-actin staining, and pit formation assays were conducted to confirm Ssa-mediated inhibition of RANKL-induced osteoclastogenesis in vitro. Ssa could promote osteoclast ferroptosis and increase mitochondrial damage by promoting lipid peroxidation, as measured by iron quantification, FerroOrange staining, Dichloro-dihydro-fluorescein diacetate, MitoSOX, malondialdehyde, glutathione, and boron-dipyrromethene 581/591 C11 assays. Pathway analysis showed that Ssa can promote osteoclasts ferroptosis by inhibiting the Nrf2/SCL7A11/GPX4 axis. Notably, we found that the ferroptosis inhibitor ferrostatin-1 and the Nrf2 activator tert-Butylhydroquinone reversed the inhibitory effects of Ssa on RANKL-induced osteoclastogenesis. In vivo, micro-computed tomography, hematoxylin and eosin staining, TRAP staining, enzyme-linked immunosorbent assays, and immunofluorescence confirmed that in rats with periodontitis induced by lipopolysaccharide, treatment with Ssa reduced alveolar bone resorption dose-dependently. The results suggested Ssa as a promising drug to treat osteolytic diseases.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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]-1β, IL-6, IL-8, IP-10, and monocyte chemotactic protein-1) in the synovial fluid relative to the control group.
UNASSIGNED: 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.

Macrophage-to-osteoclast differentiation (osteoclastogenesis) plays an essential role in tumor osteolytic bone metastasis (BM), while its specific mechanisms remain largely uncertain in lung adenocarcinoma BM. In this study, we demonstrate that integrin-binding sialoprotein (IBSP), which is highly expressed in the cancer cells from bone metastatic and primary lesions of patients with lung adenocarcinoma, can facilitate BM and directly promote macrophage-to-osteoclast differentiation independent of RANKL/M-CSF. In vivo results further suggest that osteolytic BM in lung cancer specifically relies on IBSP-induced macrophage-to-osteoclast differentiation. Mechanistically, IBSP regulates the Rac family small GTPase 1 (Rac1)-NFAT signaling pathway and mediates the forward shift of macrophage-to-osteoclast differentiation, thereby leading to early osteolysis. Moreover, inhibition of Rac1 by EHT-1864 or azathioprine in mice models can remarkably alleviate IBSP-induced BM of lung cancer. Overall, our study suggests that tumor-secreted IBSP promotes BM by inducing macrophage-to-osteoclast differentiation, with potential as an early diagnostic maker for BM, and Rac1 can be the therapeutic target for IBSP-promoted BM in lung cancer.

Introduction Surgery is the recommended treatment for medication-related osteonecrosis of the jaw (MRONJ). However, the disease may recur postoperatively. We reviewed imaging findings in patients undergoing three or more surgeries. Patients and methods One hundred fifty patients with MRONJ underwent surgery at our hospital. Here, we present the characteristics of 34 surgeries in nine patients (two men and seven women; mean age, 73.9 years) who underwent surgery at least three times. Results Three and six patients had maxillary and mandibular lesions, respectively. The primary disease was malignancy in eight patients, and denosumab was used in seven patients. All patients initially underwent either partial maxillectomy or marginal mandibulectomy, and segmental mandibulectomy was not performed. The number of surgeries ranged from three to six (average, 3.8). Healing was eventually achieved in seven cases, but not in two cases. Of the 27 unsuccessful surgeries, postoperative cone-beam computed tomography revealed no residual osteolysis, periosteal reaction, or osteosclerosis after seven surgeries and some residual lesions after 19 surgeries; imaging was not performed after one surgery. In contrast, among the seven successful surgeries, no residual osteolysis, periosteal reaction, or osteosclerosis was observed in all six cases in which postoperative computed tomography was performed. Conclusion Recurrence is more common in patients with residual areas of osteolysis, periosteal reactions, or mixed-type osteosclerosis, and including these areas in the resection is desirable.

UNASSIGNED: The Latarjet procedure was developed for the treatment of anterior shoulder instability in young, high-demand patients with attritional glenoid bone loss, whose risk of redislocation following primary dislocation may exceed 90%. Coracoid graft osteolysis and prominent screws are commonly observed in late computed tomography (CT) scans of patients who re-present following the procedure, but the clinical relevance of osteolysis in the overall Latarjet cohort is undetermined. We aimed to evaluate clinical and radiological outcomes in patients who underwent the Latarjet procedure, and to determine if severe coracoid graft osteolysis compromised clinical outcomes.
UNASSIGNED: This was a retrospective analysis of patients who underwent the open Latarjet procedure. Patients were invited via an e-questionnaire that contained a Western Ontario Shoulder Instability Index (WOSI), and queried about redislocation and reoperation since index surgery. Preoperative glenoid bone loss was calculated on CT using the best-fit circle method. Osteolysis was graded (0, screw head buried in graft; 1, screw head exposed; 2, threads exposed; 3, complete resorption/severe osteolysis) at the level of the proximal and distal screws respectively, on axial CT scans performed ≥ 12 months postoperatively.
UNASSIGNED: Between 2011 and 2022, a single surgeon performed 442 Latarjet procedures. One hundred fifty eight patients responded to the questionnaire at median (interquartile range [IQR]) 44 (27-70) months postoperatively, among whom the median (IQR) WOSI score was 352 (142-666) points (0 = best, 2100 = worst). Recurrent anterior instability occurred in 3/158 (2%) patients. One patient required reoperation for this indication. Among patients who had CT scans ≥ 12 months postoperatively (median [IQR] 40 [29-69] months), 1 patient developed severe osteolysis around both screws (WOSI = 90), 17/62 (27%) patients developed severe osteolysis around 1 screw, all of which were proximal (median [IQR] WOSI = 235 [135-644]), and 44/62 (71%) patients did not develop severe osteolysis around either screw (median [IQR] WOSI = 487 [177-815]). There were no statistically significant differences in WOSI scores between groups based on the presence of severe osteolysis.
UNASSIGNED: The Latarjet is reliable procedure that has a low rate of redislocation and reoperation. Severe coracoid graft osteolysis occurs with time, and always affects the proximal graft first. The presence of severe osteolysis did not compromise clinical outcomes.

Progressive osteolysis can occur at the cement-bone interface of joint replacements and the associated loss of fixation can lead to clinical loosening. We previously developed a rat hemiarthroplasty model that exhibited progressive loss of fixation with the development of cement-bone gaps under the tibial tray that mimicked patterns found in human arthroplasty retrievals. Here we explored the ability of a bisphosphonate (zoledronic acid, ZA) to attenuate cement-bone osteolysis and maintain implant stability. Sprague-Dawley rats (n = 59) received a poly(methylmethacrylate) cemented tibial component and were followed for up to 12 weeks. Treatment groups included peri-operative administration of ZA (ZA group), administration of ZA at 6 weeks postop (late ZA group), or vehicle (Veh group). There was a 60% reduction in the rate of cement-bone gap formation for the ZA group (0.15 mm3/week) compared to Veh group (0.38 mm3/week, p = 0.016). Late ZA prevented further progression of gap formation but did not reverse bone loss to the level achieved in the ZA group. Micromotion from five times body weight toggle loading was positively correlated with cement-bone gap volume (p = 0.009) and negatively correlated with the amount of cement in the metaphysis (p = 0.005). Reduced new bone formation and enduring nonviable bone in the epiphysis for the ZA group were found. This suggests that low bone turnover in the epiphysis may suppress the early catabolic response due to implantation, thereby maintaining better fixation in the epiphysis. This preclinical model presents compelling supporting data documenting improved maintenance of the cement-bone fixation with the use of peri-operative bisphosphonates.