Insights into Gene Regulatory Networks in Chondrocytes

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 attempts have been made to identify gene regulatory mechanisms in chondrogenesis, mainly through biochemical approaches and genetics. More recently, newly developed next-generation sequencers (NGS) have identified thousands of gene regulatory elements on a genome scale, and provided novel insights into the multiple layers of gene regulatory mechanisms, including the modes of actions of transcription factors, post-translational histone modifications, chromatin accessibility, the concept of pioneer factors, and three-dimensional chromatin architecture. In this review, we summarize the studies that have improved our understanding of the gene regulatory mechanisms in chondrogenesis, from the historical studies to the more recent works using NGS. Finally, we consider the future perspectives, including efforts to improve our understanding of the gene regulatory landscape in chondrogenesis and potential applications to the treatment of chondrocyte-related diseases.

Single-cell RNA landscape of intratumoral heterogeneity and immunosuppressive microenvironment in advanced 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.…”

SOX9 keeps growth plates and articular cartilage healthy by inhibiting chondrocyte dedifferentiation/osteoblastic redifferentiation

“…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).…”

Conservation of Zebrafish MicroRNA-145 and Its Role during Neural Crest Cell Development

“…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 ].…”