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.

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.

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.

RAC1 inhibition ameliorates IBSP-induced bone metastasis in lung adenocarcinoma.

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.

Treatment of benign maxillomandibular osteolytic lesions larger than 4 cm: A systematic review.

OBJECTIVE: This systematic review aimed to assess the different treatments of benign maxillo-mandibular radiolucent bone lesions over 4 cm to propose a management algorithm. STUDY DESIGN: A literature search was conducted using MEDLINE/PubMed, Scopus, Google Scholar, Virtual Health Library databases, and gray literature. Randomized or non-randomized clinical trials and case series with 10 or more patients with a minimum follow up of 1 year, published in French or English until August 2023, were included. The risk of bias was assessed for all papers included. RESULTS: Of 1433 records identified, 22 were included in this review, reporting data from 1364 lesions. Ameloblastoma was the most common lesion (51.22%) and mandible was the most common site (81.21%). Initial conservative treatment was prevalent (71.04%). Recurrence was higher after conservative (13.8%) than after radical treatments (6.5%). Multilocularity, cortical perforation, dental element preservation were linked to a higher recurrence risk. CONCLUSION: This study has shown importance of understanding specific characteristics and recurrence risk in benign maxillomandibular osteolytic lesions. Multidisciplinary team approval, personalized approach based on lesion type and patient are crucial. The presence of at least one risk factor could lead to therapeutic decision. Despite limitations, the study informed lesion management and provided precise recommendations.

A calvarial osteolytic lesion of probable vascular origin in a Maya juvenile from the Classic Period ( 250-900 CE).

OBJECTIVE: This case study evaluates a focal osteolytic lesion in the right sulcus sinus transversi of an isolated os occipitale. MATERIALS: The os occipitale is from a juvenile from the Cueva de Sangre at the Classic Period (250-900 CE) site of Dos Pilas, Guatemala METHODS: The lesion was examined macroscopically, microscopically, and radiographically. RESULTS: The oval lesion has a well-circumscribed margin, endocranial origin, and involves cortical destruction of the inner and outer tables. Subperiosteal bone reaction around the lesion is present on the ectocranial surface. Skeletal evidence of increased vascularity, diploë expansion, and perimortem fracture near the lesion are not observed. CONCLUSIONS: The lesion appears to reflect a response to the presence of an expansile process that has caused pressure erosion. The anatomical location of the lesion and the endocranial origin suggest a probable vascular anomaly, such as a vascular malformation. SIGNIFICANCE: This case study represents one of the few bioarchaeological evaluations of probable vascular anomaly in a juvenile. As such, it expands our knowledge about vascular anomalies in the past and provides a comparative and core reference for guiding future paleopathological investigations on cranial osteolytic lesions. LIMITATIONS: The skeletal assemblage is commingled and fragmentary preventing the assessment of the distribution of lesions across the skeleton. SUGGESTIONS FOR FUTURE RESEARCH: Further scrutiny of bioarchaeological collections is needed to better understand the distribution of vascular anomalies in the past.

Mitigating polyethylene-mediated periprosthetic tissue inflammation through MEDSAH-grafting.

Periprosthetic tissue inflammation is a challenging complication arising in joint replacement surgeries, which is often caused by wear debris from polyethylene (PE) components. In this study, we examined the potential biological effects of grafting a [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (MEDSAH) polymer onto the surface of PE through a solvent-evaporation technique. J774A.1 macrophage-like cells and primary cultured mouse osteoblasts were treated with PE powder with or without the MEDSAH coating. MEDSAH grafting on PE substantially reduced the expression of pro-inflammatory cytokines and other mediators in primary cultured mouse osteoblasts, but did not significantly impact macrophage-mediated inflammation. Our findings suggest that a MEDSAH coating on PE-based materials has potential utility in mitigating periprosthetic tissue inflammation and osteolysis and preventing aseptic loosening in total joint replacements. Further research, including large-scale clinical trials and biomechanical analyses, is needed to assess the long-term performance and clinical implications of MEDSAH-coated PE-based materials in total joint arthroplasty.

Engineered Niobium Carbide MXenzyme-Integrated Self-Adaptive Coatings Inhibiting Periprosthetic Osteolysis by Orchestrating Osteogenesis-Osteoclastogenesis Balance.

Periprosthetic osteolysis induced by the ultrahigh-molecular-weight polyethylene (UHMWPE) wear particles is a major complication associated with the sustained service of artificial joint prostheses and often necessitates revision surgery. Therefore, a smart implant with direct prevention and repair abilities is urgently developed to avoid painful revision surgery. Herein, we fabricate a phosphatidylserine- and polyethylenimine-engineered niobium carbide (Nb2C) MXenzyme-coated micro/nanostructured titanium implant (PPN@MNTi) that inhibits UHMWPE particle-induced periprosthetic osteolysis. The specific mechanism by which PPN@MNTi operates involves the bioresponsive release of nanosheets from the MNTi substrate within an osteolysis microenvironment, initiated by the cleavage of a thioketal-dopamine molecule sensitive to reactive oxygen species (ROS). Subsequently, functionalized Nb2C MXenzyme could target macrophages and escape from lysosomes, effectively scavenging intracellular ROS through its antioxidant nanozyme-mimicking activities. This further achieves the suppression of osteoclastogenesis by inhibiting NF-κB/MAPK and autophagy signaling pathways. Simultaneously, based on the synergistic effect of MXenzyme-integrated coatings and micro/nanostructured topography, the designed implant promotes the osteogenic differentiation of bone mesenchymal stem cells to regulate bone homeostasis, further achieving advanced osseointegration and alleviable periprosthetic osteolysis in vivo. This study provides a precise prevention and repair strategy of periprosthetic osteolysis, offering a paradigm for the development of smart orthopedic implants.

Hecogenin alleviates LPS-induced osteolysis via regulating pyroptosis and ROS involved Nrf2 activation.

Reactive oxidative species (ROS) generation triggers pyroptosis and induces development of inflammatory osteolysis. Hecogenin (HG) has anti-inflammatory and antioxidative property, but its effects on inflammatory osteolysis remains unclear. In our study, we investigated the mechanism of HG on pyroptosis and its effect on inflammatory osteolysis in vitro and in vivo. The impact of HG on osteoclastogenesis was evaluated using cytotoxicity, TRAcP staining and bone resorption assays. The RNA-sequencing was employed to identify potential signaling pathways, and then RT-qPCR, western blot, immunofluorescence, and ELISA were used to verify. To determine the protective effect of HG in vivo, Lipopolysaccharide (LPS)-induced animal models were utilized, along with micro-CT and histological examination. HG suppressed RANKL-induced osteoclast differentiation, bone resorption, NFATc1 activity and downstream factors. RNA-sequencing results showed that HG inhibited osteoclastogenesis by modulating the inflammatory response and macrophage polarization. Furthermore, HG inhibited the NF-κB pathway, and deactivated the NLRP3 inflammasome. HG activated the expression of nuclear factor E2-related factor 2 (Nrf2) to eliminate ROS generation. Importantly, the inhibitory effect of HG on NLRP3 inflammasome could be reversed by treatment with the Nrf2 inhibitor ML385. In vivo, HG prevented the mice against LPS-induced osteolysis by suppressing osteoclastogenesis and inflammatory factors. In conclusion, HG could activate Nrf2 to eliminate ROS generation, inactivate NLRP3 inflammasome and inhibit pyroptosis, thereby suppressing osteoclastogenesis in vitro and alleviating inflammatory osteolysis in vivo, which indicating that HG might be a promising candidate to treat inflammatory osteolysis.

BIGH3 mediates apoptosis and gap junction failure in osteocytes during renal cell carcinoma bone metastasis progression.

Renal cell carcinoma (RCC) bone metastatis progression is driven by crosstalk between tumor cells and the bone microenvironment, which includes osteoblasts, osteoclasts, and osteocytes. RCC bone metastases (RCCBM) are predominantly osteolytic and resistant to antiresorptive therapy. The molecular mechanisms underlying pathologic osteolysis and disruption of bone homeostasis remain incompletely understood. We previously reported that BIGH3/TGFBI (transforming growth factor-beta-induced protein ig-h3, shortened to BIGH3 henceforth) secreted by colonizing RCC cells drives osteolysis by inhibiting osteoblast differentiation, impairing healing of osteolytic lesions, which is reversible with osteoanabolic agents. Here, we report that BIGH3 induces osteocyte apoptosis in both human RCCBM tissue specimens and in a preclinical mouse model. We also demonstrate that BIGH3 reduces Cx43 expression, blocking gap junction (GJ) function and osteocyte network communication. BIGH3-mediated GJ inhibition is blocked by the lysosomal inhibitor hydroxychloroquine (HCQ), but not osteoanabolic agents. Our results broaden the understanding of pathologic osteolysis in RCCBM and indicate that targeting the BIGH3 mechanism could be a combinational strategy for the treatment of RCCBM-induced bone disease that overcomes the limited efficacy of antiresorptives that target osteoclasts.

diABZI and poly(I:C) inhibit osteoclastic bone resorption by inducing IRF7 and IFIT3.

Type I interferons (IFN-I) are pleiotropic factors endowed with multiple activities that play important roles in innate and adaptive immunity. Although many studies indicate that IFN-I inducers exert favorable effects on broad-spectrum antivirus, immunomodulation, and anti-tumor activities by inducing endogenous IFN-I and IFN-stimulated genes, their function in bone homeostasis still needs further exploration. Here, our study demonstrates 2 distinct IFN-I inducers, diABZI and poly(I:C), as potential therapeutics to alleviate osteolysis and osteoporosis. First, IFN-I inducers suppress the genes that control osteoclast (OC) differentiation and activity in vitro. Moreover, diABZI alleviates bone loss in Ti particle-induced osteolysis and ovariectomized -induced osteoporosis in vivo by inhibiting OC differentiation and function. In addition, the inhibitory effects of IFN-I inducers on OC differentiation are not observed in macrophages derived from Ifnar1-/-mice, which indicate that the suppressive effect of IFN-I inducers on OC is IFNAR-dependent. Mechanistically, RNAi-mediated silencing of IRF7 and IFIT3 in OC precursors impairs the suppressive effect of the IFN-I inducers on OC differentiation. Taken together, these results demonstrate that IFN-I inducers play a protective role in bone turnover by limiting osteoclastogenesis and bone resorption through the induction of OC-specific mediators via the IFN-I signaling pathway.

OCs are responsible for bone resorption, and their excessive differentiation and enhanced activity will lead to bone resorption diseases such as osteoporosis and osteolysis. Here, our study demonstrates 2 distinct IFN-I inducers, diABZI and poly(I:C), as potential therapeutics to alleviate osteolysis and osteoporosis. IFN-I inducers suppress OC differentiation, and particularly diABZI alleviates bone loss in osteolysis and osteoporosis mouse models. Taken together, IFN-I inducers play a protective role in bone turnover by limiting osteoclastogenesis and bone resorption through the induction of OC-specific mediators via the IFN-I signaling pathway. Our in-depth and comprehensive discovery of the IFN-I inducer would provide new insight into OC biology and therapeutic targets for osteoclastic bone resorption diseases.

The miR-29-3p family suppresses inflammatory osteolysis.

Osteoclasts are the cells primarily responsible for inflammation-induced bone loss, as is particularly seen in rheumatoid arthritis. Increasing evidence suggests that osteoclasts formed under homeostatic versus inflammatory conditions may differ in phenotype. While microRNA-29-3p family members (miR-29a-3p, miR-29b-3p, miR-29c-3p) promote the function of RANKL-induced osteoclasts, the role of miR-29-3p during inflammatory TNF-α-induced osteoclastogenesis is unknown. We used bulk RNA-seq, histology, qRT-PCR, reporter assays, and western blot analysis to examine bone marrow monocytic cell cultures and tissue from male mice in which the function of miR-29-3p family members was decreased by expression of a miR-29-3p tough decoy (TuD) competitive inhibitor in the myeloid lineage (LysM-cre). We found that RANKL-treated monocytic cells expressing the miR-29-3p TuD developed a hypercytokinemia/proinflammatory gene expression profile in vitro, which is associated with macrophages. These data support the concept that miR-29-3p suppresses macrophage lineage commitment and may have anti-inflammatory effects. In correlation, when miR-29-3p activity was decreased, TNF-α-induced osteoclast formation was accentuated in an in vivo model of localized osteolysis and in a cell-autonomous manner in vitro. Further, miR-29-3p targets mouse TNF receptor 1 (TNFR1/Tnfrsf1a), an evolutionarily conserved regulatory mechanism, which likely contributes to the increased TNF-α signaling sensitivity observed in the miR-29-3p decoy cells. Whereas our previous studies demonstrated that the miR-29-3p family promotes RANKL-induced bone resorption, the present work shows that miR-29-3p dampens TNF-α-induced osteoclastogenesis, indicating that miR-29-3p has pleiotropic effects in bone homeostasis and inflammatory osteolysis. Our data supports the concept that the knockdown of miR-29-3p activity could prime myeloid cells to respond to an inflammatory challenge and potentially shift lineage commitment toward macrophage, making the miR-29-3p family a potential therapeutic target for modulating inflammatory response.

Interrogating Estrogen Signaling Pathways in Human ER-Positive Breast Cancer Cells Forming Bone Metastases in Mice.

Breast cancer bone metastases (BMET) are incurable, primarily osteolytic, and occur most commonly in estrogen receptor-α positive (ER+) breast cancer. ER+ human breast cancer BMET modeling in mice has demonstrated an estrogen (E2)-dependent increase in tumor-associated osteolysis and bone-resorbing osteoclasts, independent of estrogenic effects on tumor proliferation or bone turnover, suggesting a possible mechanistic link between tumoral ERα-driven osteolysis and ER+ bone progression. To explore this question, inducible secretion of the osteolytic factor, parathyroid hormone-related protein (PTHrP), was utilized as an in vitro screening bioassay to query the osteolytic potential of estrogen receptor- and signaling pathway-specific ligands in BMET-forming ER+ human breast cancer cells expressing ERα, ERß, and G protein-coupled ER. After identifying genomic ERα signaling, also responsibility for estrogen's proliferative effects, as necessary and sufficient for osteolytic PTHrP secretion, in vivo effects of a genomic-only ER agonist, estetrol (E4), on osteolytic ER+ BMET progression were examined. Surprisingly, while pharmacologic effects of E4 on estrogen-dependent tissues, including bone, were evident, E4 did not support osteolytic BMET progression (vs robust E2 effects), suggesting an important role for nongenomic ER signaling in ER+ metastatic progression at this site. Because bone effects of E4 did not completely recapitulate those of E2, the relative importance of nongenomic ER signaling in tumor vs bone cannot be ascertained here. Nonetheless, these intriguing findings suggest that targeted manipulation of estrogen signaling to mitigate ER+ metastatic progression in bone may require a nuanced approach, considering genomic and nongenomic effects of ER signaling on both sides of the tumor/bone interface.

Kaempferol attenuates particle-induced osteogenic impairment by regulating ER stress via the IRE1α-XBP1s pathway.

Periprosthetic osteolysis and subsequent aseptic loosening are the primary causes of failure following total joint arthroplasty. Wear particle-induced osteogenic impairment is recognized as an important contributing factor in the development of osteolysis, with endoplasmic reticulum (ER) stress emerging as a pivotal underlying mechanism. Hence, searching for potential therapeutic targets and agents capable of modulating ER stress in osteoblasts is crucial for preventing aseptic loosening. Kaempferol (KAE), a natural flavonol compound, has shown promising osteoprotective effects and anti-ER stress properties in diverse diseases. However, the influence of KAE on ER stress-mediated osteogenic impairment induced by wear particles remains unclear. In this study, we observed that KAE effectively relieved TiAl6V4 particles-induced osteolysis by improving osteogenesis in a mouse calvarial model. Furthermore, we demonstrated that KAE could attenuate ER stress-mediated apoptosis in osteoblasts exposed to TiAl6V4 particles, both in vitro and in vivo. Mechanistically, our results revealed that KAE mitigated ER stress-mediated apoptosis by upregulating the IRE1α-XBP1s pathway while concurrently partially inhibiting the IRE1α-regulated RIDD and JNK activation. Collectively, our findings suggest that KAE is a prospective therapeutic agent for treating wear particle-induced osteolysis and highlight the IRE1α-XBP1s pathway as a potential therapeutic target for preventing aseptic loosening.

Fourier-transform infrared spectroscopy imaging is a useful adjunct to routine histopathology to identify failure of polyethylene inlays in revision total hip arthroplasty.

The use of highly crosslinked ultra-high molecular weight polyethylene (XLPE) has significantly reduced the volumetric wear of acetabular liners, thereby reducing the incidence of osteolysis. However, contemporary components tend to generate smaller wear particles, which can no longer be identified using conventional histology. This technical limitation can result in imprecise diagnosis. Here, we report on two uncemented total hip arthroplasty cases (~7 years in situ) revised for periprosthetic fracture of the femur and femoral loosening, respectively. Both liners exhibited prominent wear. The retrieved pseudocapsular tissue exhibited a strong macrophage infiltration without microscopically identifiable polyethylene particles. Yet, using Fourier-transform infrared micro-spectroscopic imaging (FTIR-I), we demonstrated the prominent intracellular accumulation of polyethylene debris in both cases. This study shows that particle induced osteolysis can still occur with XLPE liners, even under 10 years in situ. Furthermore, we demonstrate the difficulty of determining the presence of polyethylene debris within periprosthetic tissue. Considering the potentially increased bioactivity of finer particles from XLPE compared to conventional liners, an accurate detection method is required, and new histopathological hallmarks of particle induced osteolysis are needed. FTIR-I is a great tool to that end and can help the accurate determination of foreign body tissue responses.

[Rare differential diagnosis of an osteolytic lesion of the mandible in a young adult]. / Seltene Differenzialdiagnose bei osteolytischer Läsion des Unterkiefers einer jungen Erwachsenen.

We report a rarely occurring hematologic neoplasm in a young adult. Hematologic neoplasms were first described in 2008 and are now included in both accepted tumor classification systems, i.e., International Consensus Classification and World Health Organization. This hematologic neoplasm shows a characteristic ALK positivity in immunohistochemical examination and correspondingly, ALK fusion genes in the molecular analysis. Pathologists should be aware of this entity, particularly as it is challenging to differentiate from other more frequent neoplasms of the same disease group or mesenchymal neoplasm with ALK aberration.

Rapid Selenoprotein Activation by Selenium Nanoparticles to Suppresses Osteoclastogenesis and Pathological Bone Loss.

Osteoclast hyperactivation stands as a significant pathological factor contributing to the emergence of bone disorders driven by heightened oxidative stress levels. The modulation of the redox balance to scavenge reactive oxygen species emerges as a viable approach to addressing this concern. Selenoproteins, characterized by selenocysteine (SeCys2) as the active center, are crucial for selenium-based antioxidative stress therapy for inflammatory diseases. This study reveals that surface-active elemental selenium (Se) nanoparticles, particularly lentinan-Se (LNT-Se), exhibit enhanced cellular accumulation and accelerated metabolism to SeCys2, the primary active Se form in biological systems. Consequently, LNT-Se demonstrates significant inhibition of osteoclastogenesis. Furthermore, in vivo studies underscore the superior therapeutic efficacy of LNT-Se over SeCys2, potentially attributable to the enhanced stability and safety profile of LNT-Se. Specifically, LNT-Se effectively modulates the expression of the selenoprotein GPx1, thereby exerting regulatory control over osteoclastogenesis inhibition, and the prevention of osteolysis. In summary, these results suggest that the prompt activation of selenoproteins by Se nanoparticles serves to suppress osteoclastogenesis and pathological bone loss by upregulating GPx1. Moreover, the utilization of bioactive Se species presents a promising avenue for effectively managing bone disorders.

A mechanobiological model of bone metastasis reveals that mechanical stimulation inhibits the pro-osteolytic effects of breast cancer cells.

Bone is highly susceptible to cancer metastasis, and both tumor and bone cells enable tumor invasion through a "vicious cycle" of biochemical signaling. Tumor metastasis into bone also alters biophysical cues to both tumor and bone cells, which are highly sensitive to their mechanical environment. However, the mechanobiological feedback between these cells that perpetuate this cycle has not been studied. Here, we develop highly advanced in vitro and computational models to provide an advanced understanding of how tumor growth is regulated by the synergistic influence of tumor-bone cell signaling and mechanobiological cues. In particular, we develop a multicellular healthy and metastatic bone model that can account for physiological mechanical signals within a custom bioreactor. These models successfully recapitulated mineralization, mechanobiological responses, osteolysis, and metastatic activity. Ultimately, we demonstrate that mechanical stimulus provided protective effects against tumor-induced osteolysis, confirming the importance of mechanobiological factors in bone metastasis development.

Morusin inhibits breast cancer-induced osteolysis by decreasing phosphatidylinositol 3-kinase (PI3K)-mTOR signalling.

Bone metastases caused by breast cancer pose a major challenge to the successful treatment of breast cancer patients. Many researchers have suggested that herbal medicines are extremely effective at preventing and treating cancer-associated osteolysis. Previous studies have revealed that Morusin (MOR) is cytotoxic to many cancer cells ex vivo. Nevertheless, how MOR contributes to osteolysis induced by breast cancer is still unknown, and the potential mechanism of action against osteolysis is worthy of further study. The protective effect and molecular mechanism of MOR in inhibiting breast cancer cell-induced osteolysis were verified by experiments and network pharmacology. Cell function was assessed by cell proliferation, osteoclast (OC) formation, bone resorption, and phalloidin staining. Tumour growth was examined by micro-CT scanning in vivo. To identify potential MOR treatments, the active ingredient-target pathway of breast cancer was screened using network pharmacology and molecular docking approaches. This study is the first to report that MOR can prevent osteolysis induced by breast cancer cells. Specifically, our results revealed that MOR inhibits RANKL-induced osteoclastogenesis and restrains the proliferation, invasion and migration of MDA-MB-231 breast cells through restraining the PI3K/AKT/MTOR signalling pathway. Notably, MOR prevented bone loss caused by breast cancer cell-induced osteolysis in vivo, indicating that MOR inhibited the development of OCs and the resorption of bone, which are essential for cancer cell-associated bone distraction. This study showed that MOR treatment inhibited osteolysis induced by breast cancer in vivo. MOR inhibited OC differentiation and bone resorption ex vivo and in vivo and might be a potential drug candidate for treating breast cancer-induced osteolysis.

A case report of multicentric carpotarsal osteolysis syndrome: Depiction of a debilitating disease course.

Multicentric carpotarsal osteolysis syndrome (MCTO) is a rare skeletal disorder characterized by progressive osteolysis involving the carpal and tarsal bones, and often associated with nephropathy. It is caused by heterozygous mutation in the MAF bZIP transcription factor B (MAFB) gene. Heterogeneous clinical manifestation and wide spectrum of disease severity have been observed in patients with MCTO. Here, we report a case of a male patient who presented with kidney failure in childhood with progressive disabling skeletal deformity. He was diagnosed with MCTO at 31-years-old, where a de novo pathogenic heterozygous variant in NM_005461.5:c.212C>A: p.(Pro71His) of the MAFB gene was identified. While there has been little data on the long-term prognosis and life expectancy of this disease, this case report sheds light on the debilitating disease course with multiple significant morbidities of a patient with MCTO throughout his lifetime of 33 years.