Mmp-13 deletion in cells of the mesenchymal lineage increases bone mass, decreases endocortical osteoclast number and attenuates the cortical bone loss caused by estrogen deficiency in mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE191214 | GEO | 2022/06/01
REPOSITORIES: GEO
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Project description:Mmp-13 deletion in cells of the mesenchymal lineage increases bone mass, decreases endocortical osteoclast number and attenuates the cortical bone loss caused by estrogen deficiency in mice
| PRJNA790615 | ENA
Project description:INTRODUCTION: The increased bone degradation in osteolytic metastases depends on stimulation of mature osteoclasts and on continuous differentiation of new pre-osteoclasts. Metalloproteinases (MMP)-13 is expressed in a broad range of primary malignant tumours and it is emerging as a novel biomarker. Recent data suggest a direct role of MMP-13 in dissolving bone matrix complementing the activity of MMP-9 and other enzymes. Tumour-microenvironment interactions alter gene expression in malignant breast tumour cells promoting osteolytic bone metastasis. Gene expression profiles revealed that MMP-13 was among the up-regulated genes in tumour-bone interface and its abrogation reduced bone erosion. The precise mechanism remained not fully understood. Our purpose was to further investigate the mechanistic role of MMP-13 in bone osteolytic lesions. METHODS: MDA-MB-231 breast cancer cells that express MMP-13 were used as a model for in vitro and in vivo experiments. Conditioned media from MDA-MB-231 cells were added to peripheral blood mononuclear cultures to monitor pre-osteoclast differentiation and activation. Bone erosion was evaluated after injection of MMP-13-silenced MDA-MB-231 cells into nude mice femurs. RESULTS: MMP-13 was co-expressed by human breast tumour bone metastases with its activator MT1-MMP. MMP-13 was up-regulated in breast cancer cells after in vitro stimulation with IL-8 and was responsible for increased bone resorption and osteoclastogenesis, both of which were reduced by MMP inhibitors. We hypothesized that MMP-13 might be directly involved in the loop promoting pre-osteoclast differentiation and activity. We obtained further evidence for a direct role of MMP-13 in bone metastasis by a silencing approach: conditioned media from MDA-MB-231 after MMP-13 abrogation or co-cultivation of silenced cells with pre-osteoclast were unable to increase pre-osteoclast differentiation and resorption activity. MMP-13 activated pre-MMP-9 and promoted the cleavage of galectin-3, a suppressor of osteoclastogenesis, thus contributing to pre-osteoclast differentiation. Accordingly, MMP-13 abrogation in tumour cells injected into the femurs of nude mice reduced the differentiation of TRAP positive cells in bone marrow and within the tumour mass as well as bone erosion. CONCLUSIONS: These results indicate that within the inflammatory bone microenvironment MMP-13 production was up-regulated in breast tumour cells leading to increased pre-osteoclast differentiation and their subsequent activation.
| S-EPMC3262218 | biostudies-other
Project description:Metabolic bone diseases, such as osteoporosis, typically reflect an increase in the number and activity of bone-resorbing osteoclasts that result in a loss of bone mass. Inflammatory mediators have been identified as drivers of both osteoclast formation and activity. The IL-17 family of inflammatory cytokines has gained attention as important contributors to both bone formation and resorption. The majority of IL-17 cytokines signal through receptor complexes containing IL-17a receptor (IL-17ra); however, the role of IL-17ra signaling in osteoclasts remains elusive. In this study, we conditionally deleted Il17ra in osteoclast precursors using LysM-Cre and evaluated the phenotypes of skeletally mature male and female conditional knockout and control mice. The conditional knockout mice displayed an increase in trabecular bone microarchitecture in both the appendicular and axial skeleton. Assessment of osteoclast formation in vitro revealed that deletion of Il17ra decreased osteoclast number, which was confirmed in vivo using histomorphometry. This phenotype was likely driven by a lower abundance of osteoclast precursors in IL-17ra conditional knockout mice. This study suggests that IL-17ra signaling in preosteoclasts can contribute to osteoclast formation and subsequent bone loss.
| S-EPMC10084774 | biostudies-literature
Project description:Integrin signaling plays a fundamental role in the establishment of focal adhesions and the subsequent formation of invadopodia in malignant cancer cells. Invadopodia facilitate localized adhesion and degradation of the extracellular matrix (ECM), which promote tumour cell invasion and metastasis. Degradation of ECM components is often driven by membrane type-1 matrix metalloproteinase (MT1-MMP), and we have recently shown that regulation of enzyme internalization is dependent on signaling downstream of β1 integrin. Phosphorylation of the cytoplasmic tail of MT1-MMP is required for its internalization and delivery to Rab5-marked early endosomes, where it is then able to be recycled to new sites of invadopodia formation and promote invasion. Here we found that inhibition of β1 integrin, using the antibody AIIB2, inhibited the internalization and recycling of MT1-MMP that is necessary to support long-term cellular invasion. MT1-MMP and β1 integrin were sequestered at the cell surface when β1-integrin was inhibited, and their association under these conditions was detected using immunoprecipitation and mass spectrometry analysis. Sequestration of β1 integrin and MT1-MMP at the cell surface resulted in the formation of large invadopodia and local ECM degradation; however, the impaired internalization and recycling of MT1-MMP and β1 integrin ultimately led to a loss of invasive behaviour.
2022-12-22 | PXD024000 | Pride
Project description:Osteoclast stimulation factor 1 (OSTF1) is an SH3-domain containing protein that was initially identified as a factor involved in the indirect activation of osteoclasts. It has been linked to spinal muscular atrophy in humans through its interaction with SMN1, and is one of six genes deleted in a human developmental microdeletion syndrome. To investigate the function of OSTF1, we generated an Ostf1 knockout mouse model, with exons 3 and 4 of Ostf1 replaced by a LacZ orf. Extensive X-Gal staining was performed to examine the developmental and adult expression pattern, followed by phenotyping. We show widespread expression of the gene in the vasculature of most organs and in a number of cell types in adult and embryonic mouse tissues. Furthermore, whilst SHIRPA testing revealed no behavioural defects, we demonstrate increased trabecular mass in the long bones, confirming a role for OSTF1 in bone development.
| S-EPMC5680368 | biostudies-literature
Project description:Multiple myeloma (MM) cells secrete osteoclastogenic factors that promote osteolytic lesions; however, the identity of these factors is largely unknown. Here, we performed a screen of human myeloma cells to identify pro-osteoclastogenic agents that could potentially serve as therapeutic targets for ameliorating MM-associated bone disease. We found that myeloma cells express high levels of the matrix metalloproteinase MMP-13 and determined that MMP-13 directly enhances osteoclast multinucleation and bone-resorptive activity by triggering upregulation of the cell fusogen DC-STAMP. Moreover, this effect was independent of the proteolytic activity of the enzyme. Further, in mouse xenograft models, silencing MMP-13 expression in myeloma cells inhibited the development of osteolytic lesions. In patient cohorts, MMP-13 expression was localized to BM-associated myeloma cells, while elevated MMP-13 serum levels were able to correctly predict the presence of active bone disease. Together, these data demonstrate that MMP-13 is critical for the development of osteolytic lesions in MM and that targeting the MMP-13 protein - rather than its catalytic activity - constitutes a potential approach to mitigating bone disease in affected patients.
| S-EPMC4855918 | biostudies-literature
Project description:We investigated the skeletal effects of conditional overexpression of Runx1 in preosteoclasts by crossing novel Runx1 gain-of-function mice (Rosa26-LSL-Runx1) with LysM-Cre transgenic mice.
2022-10-24 | GSE216312 | GEO
Project description:Many metabolic bone diseases arise as a result excessive osteoclastic bone resorption, which has motivated efforts to identify new molecular targets that can inhibit the formation or activity of these bone-resorbing cells. Mounting evidence indicates that the transcription factor Runx1 acts as a transcriptional repressor of osteoclast formation. Prior studies using a conditional knockout approach suggested that Runx1 in osteoclast precursors acts as an inhibitor of osteoclastogenesis; however, the effects of upregulation of Runx1 on osteoclast formation remain unknown. In this study, we investigated the skeletal effects of conditional overexpression of Runx1 in preosteoclasts by crossing novel Runx1 gain-of-function mice (Rosa26-LSL-Runx1) with LysM-Cre transgenic mice. We observed a sex-dependent effect whereby overexpression of Runx1 in female mice increased trabecular bone microarchitectural indices and improved torsion biomechanical properties. These effects were likely mediated by delayed osteoclastogenesis and decreased bone resorption. Transcriptomics analyses during osteoclastogenesis revealed a distinct transcriptomic profile in the Runx1-overexpressing cells, with enrichment of genes related to redox signaling, apoptosis, osteoclast differentiation, and bone remodeling. These data further confirm the antiosteoclastogenic activities of Runx1 and provide new insight into the molecular targets that may mediate these effects.
| S-EPMC9337273 | biostudies-literature
Project description:Invasion of bladder cancer (BC) cells from the mucosa into the muscle layer is canonical for BC progression while phospholipase D isoform 1 (PLD1) is known to mediate development of cancer through phosphatidic acid (PA) production. We therefore used in silico, in vitro and in vivo approaches to detail the effect of PLD1 on BC invasion. In BC patients, higher levels of PLD1 expression were associated with poor prognosis. PLD1 knockdown significantly suppressed cellular invasion by human BC cells and matrix metalloproteinase-13 (MMP-13) was observed to be an invasion mediator gene. In our mouse bladder carcinogenesis model, the development of invasive BCs was suppressed by PLD1 knockout and a global transcriptomic analysis in this model indicated MMP-13 as a potential tumor invasion gene with NF-kB (nuclear factor-kB) as its transcription regulator. Furthermore, PA administration increased both MMP-13 expression and NF-kB p65 phosphorylation levels. Collectively, we demonstrate that PLD1 promotes tumor invasion of BC by regulation of MMP-13 expression via phosphorylation of NF-kB p65. Our results suggest that PLD1 is a potential therapeutic target to prevent progression in BC patients.
2022-04-05 | GSE166004 | GEO
Project description:MT1-MMP and MT2-MMP double deficiency in mice leads to development of a placental defect resulting in embryonic death after E10.5. The protein substrate for these two proteases in placenta is unknown, which poses an obstacle in uncovering of molecular mechanism behind the observed placental defect. In search for a potential substrate for these two proteases in placenta we have employed whole genome microarray expression profiling as a discovery platform to identify genes, expression of which might be affected by double MMP deficiency. Fetal parts of mouse placentas were isolated from E10.5 placentas of different genotypes for MT1- and MT2-MMP.
2010-03-09 | E-GEOD-18604 | biostudies-arrayexpress