Abstract:Chondrogenesis is a key developmental process that molds the framework of our body and generates the skeletal tissues by coupling with osteogenesis. The developmental processes are well-coordinated by spatiotemporal gene expressions, which are hardwired with gene regulatory elements. Those elements exist as thousands of modules of DNA sequences on the genome. Transcription factors function as key regulatory proteins by binding to regulatory elements and recruiting cofactors. Over the past 30 years, extensive a… Show more
“…In addition, we found both the chondroblastic and osteoblastic malignant cells were localized in the primary site while only the uniformed osteoblastic malignant cells were detected in the lung metastasis lesions of the chondroblastic OS of patient BC17, suggesting that the osteoblastic OS cells have more aggressive tumoral activities and are capable of distant metastasis compared to the corresponding chondroblastic tumor cells. This is supported by the reports that the malignant chondroblastic cells grew slow and were less sensitive to the chemotherapy treatments than malignant osteoblastic cells 71 . These results suggested that chemotherapy reagents that targeting both the chondroblastic and osteoblastic tumor cells are warranted for efficient treatment for chondroblastic OS in clinic.…”
Osteosarcoma is the most frequent primary bone tumor with poor prognosis. Through RNA-sequencing of 100,987 individual cells from 7 primary, 2 recurrent, and 2 lung metastatic osteosarcoma lesions, 11 major cell clusters are identified based on unbiased clustering of gene expression profiles and canonical markers. The transcriptomic properties, regulators and dynamics of osteosarcoma malignant cells together with their tumor microenvironment particularly stromal and immune cells are characterized. The transdifferentiation of malignant osteoblastic cells from malignant chondroblastic cells is revealed by analyses of inferred copy-number variation and trajectory. A proinflammatory FABP4+ macrophages infiltration is noticed in lung metastatic osteosarcoma lesions. Lower osteoclasts infiltration is observed in chondroblastic, recurrent and lung metastatic osteosarcoma lesions compared to primary osteoblastic osteosarcoma lesions. Importantly, TIGIT blockade enhances the cytotoxicity effects of the primary CD3+ T cells with high proportion of TIGIT+ cells against osteosarcoma. These results present a single-cell atlas, explore intratumor heterogeneity, and provide potential therapeutic targets for osteosarcoma.
“…In addition, we found both the chondroblastic and osteoblastic malignant cells were localized in the primary site while only the uniformed osteoblastic malignant cells were detected in the lung metastasis lesions of the chondroblastic OS of patient BC17, suggesting that the osteoblastic OS cells have more aggressive tumoral activities and are capable of distant metastasis compared to the corresponding chondroblastic tumor cells. This is supported by the reports that the malignant chondroblastic cells grew slow and were less sensitive to the chemotherapy treatments than malignant osteoblastic cells 71 . These results suggested that chemotherapy reagents that targeting both the chondroblastic and osteoblastic tumor cells are warranted for efficient treatment for chondroblastic OS in clinic.…”
Osteosarcoma is the most frequent primary bone tumor with poor prognosis. Through RNA-sequencing of 100,987 individual cells from 7 primary, 2 recurrent, and 2 lung metastatic osteosarcoma lesions, 11 major cell clusters are identified based on unbiased clustering of gene expression profiles and canonical markers. The transcriptomic properties, regulators and dynamics of osteosarcoma malignant cells together with their tumor microenvironment particularly stromal and immune cells are characterized. The transdifferentiation of malignant osteoblastic cells from malignant chondroblastic cells is revealed by analyses of inferred copy-number variation and trajectory. A proinflammatory FABP4+ macrophages infiltration is noticed in lung metastatic osteosarcoma lesions. Lower osteoclasts infiltration is observed in chondroblastic, recurrent and lung metastatic osteosarcoma lesions compared to primary osteoblastic osteosarcoma lesions. Importantly, TIGIT blockade enhances the cytotoxicity effects of the primary CD3+ T cells with high proportion of TIGIT+ cells against osteosarcoma. These results present a single-cell atlas, explore intratumor heterogeneity, and provide potential therapeutic targets for osteosarcoma.
“…Since SOX9 heterozygous mutations were linked to campomelic dysplasia, a perinatally lethal skeletal malformation disease (12,13), studies in model systems have revealed that SOX9 is a master chondrogenic transcription factor (14,15). It may not be a pioneer factor opening chromatin at specific loci, but it potently transactivates PC genes and thereby drives embryonic chondrogenesis (16)(17)(18)(19).…”
Cartilage is essential throughout vertebrate life. It starts developing in embryos when osteochondroprogenitor cells commit to chondrogenesis, activate a pancartilaginous program to form cartilaginous skeletal primordia, and also embrace a growth-plate program to drive skeletal growth or an articular program to build permanent joint cartilage. Various forms of cartilage malformation and degeneration diseases afflict humans, but underlying mechanisms are still incompletely understood and treatment options suboptimal. The transcription factor SOX9 is required for embryonic chondrogenesis, but its postnatal roles remain unclear, despite evidence that it is down-regulated in osteoarthritis and heterozygously inactivated in campomelic dysplasia, a severe skeletal dysplasia characterized postnatally by small stature and kyphoscoliosis. Using conditional knockout mice and high-throughput sequencing assays, we show here that SOX9 is required postnatally to prevent growth-plate closure and preosteoarthritic deterioration of articular cartilage. Its deficiency prompts growth-plate chondrocytes at all stages to swiftly reach a terminal/dedifferentiated stage marked by expression of chondrocyte-specific (Mgp) and progenitor-specific (Nt5e and Sox4) genes. Up-regulation of osteogenic genes (Runx2, Sp7, and Postn) and overt osteoblastogenesis quickly ensue. SOX9 deficiency does not perturb the articular program, except in load-bearing regions, where it also provokes chondrocyte-to-osteoblast conversion via a progenitor stage. Pathway analyses support roles for SOX9 in controlling TGFβ and BMP signaling activities during this cell lineage transition. Altogether, these findings deepen our current understanding of the cellular and molecular mechanisms that specifically ensure lifelong growth-plate and articular cartilage vigor by identifying osteogenic plasticity of growth-plate and articular chondrocytes and a SOX9-countered chondrocyte dedifferentiation/osteoblast redifferentiation process.
“…SOX9 defects in humans lead to campomelic dysplasia characterized by major defects in cartilage and bone [ 10 ]. Although much is understood about how SOX9 regulates cartilage matrix synthesis and hence joint function, less is known about the mechanisms controlling its own expression [ 11 , 12 ]. Some evidence suggests that miR-145 targets and suppresses the expression of Sox9, inhibiting chondrogenic differentiation of murine embryonic mesenchymal cells, as well as critically affecting human articular chondrocyte function [ 13 , 14 ].…”
The neural crest is a multipotent cell population that develops from the dorsal neural fold of vertebrate embryos in order to migrate extensively and differentiate into a variety of tissues. A number of gene regulatory networks coordinating neural crest cell specification and differentiation have been extensively studied to date. Although several publications suggest a common role for microRNA-145 (miR-145) in molecular reprogramming for cell cycle regulation and/or cellular differentiation, little is known about its role during in vivo cranial neural crest development. By modifying miR-145 levels in zebrafish embryos, abnormal craniofacial development and aberrant pigmentation phenotypes were detected. By whole-mount in situ hybridization, changes in expression patterns of col2a1a and Sry-related HMG box (Sox) transcription factors sox9a and sox9b were observed in overexpressed miR-145 embryos. In agreement, zebrafish sox9b expression was downregulated by miR-145 overexpression. In silico and in vivo analysis of the sox9b 3′UTR revealed a conserved potential miR-145 binding site likely involved in its post-transcriptional regulation. Based on these findings, we speculate that miR-145 participates in the gene regulatory network governing zebrafish chondrocyte differentiation by controlling sox9b expression.
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