Scholarlink

Background <p>ADAMTS-2 is a key extracellular matrix (ECM) remodeling enzyme increasingly implicated in osteosarcoma biology. Although ADAMTS-2 is known to participate in collagen processing and ECM turnover, the upstream inflammatory cues and transcriptional mechanisms regulating its expression in osteosarcoma remain unclear. Tumor necrosis factor-α (TNF-α), a dominant pro-inflammatory cytokine within the osteosarcoma microenvironment, represents a strong candidate regulator due to its ability to activate several pathways. This study aimed to elucidate the TNF-α–ADAMTS-2 regulatory axis at mechanistic levels.</p> Methods and results <p>Gene expression profiling revealed that ADAMTS-2 is significantly upregulated in osteosarcoma tissues compared with normal bone and is associated with ECM disassembly and collagen fibril organization pathways. Functional assays in Saos-2 cells demonstrated that TNF-α stimulation markedly increased ADAMTS-2 mRNA (~ 17-fold) and protein levels (~ twofold). Promoter activity assays showed strong TNF-α–mediated activation, with the highest induction in the − 180/ + 112 region. Pharmacological inhibition experiments revealed that MEK, PI3K, JNK, and NF-κB pathways are all required for TNF-α-induced ADAMTS-2 transcription. In silico motif analysis identified STAT3 and NF-κB binding elements within the promoter, and electrophoretic mobility shift assays supported the interaction of these transcription factors with specific promoter regions.</p> Conclusions <p>This study provides the first mechanistic evidence that TNF-α regulates ADAMTS-2 expression through the coordinated activation of multiple signaling pathways and the engagement of STAT3 and NF-κB transcription factors at the promoter. These findings uncover a previously uncharacterized inflammatory regulatory axis linking TNF-α signaling to ECM remodeling and highlight ADAMTS-2 as a potential mediator of osteosarcoma progression.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

TNF-α orchestrates ADAM metallopeptidase with thrombospondin type 1 motif 2 upregulation and extracellular matrix remodeling through multimodal signaling in osteosarcoma cells

  • 期刊论文

  • 发表日期：

    2026年2月2日

查看全文
  • Ehed Muhammed Aymaz,
  • Meltem Alper,
  • Yasemin Kalfa,
  • Feray Kockar

摘要

Background

ADAMTS-2 is a key extracellular matrix (ECM) remodeling enzyme increasingly implicated in osteosarcoma biology. Although ADAMTS-2 is known to participate in collagen processing and ECM turnover, the upstream inflammatory cues and transcriptional mechanisms regulating its expression in osteosarcoma remain unclear. Tumor necrosis factor-α (TNF-α), a dominant pro-inflammatory cytokine within the osteosarcoma microenvironment, represents a strong candidate regulator due to its ability to activate several pathways. This study aimed to elucidate the TNF-α–ADAMTS-2 regulatory axis at mechanistic levels.

Methods and results

Gene expression profiling revealed that ADAMTS-2 is significantly upregulated in osteosarcoma tissues compared with normal bone and is associated with ECM disassembly and collagen fibril organization pathways. Functional assays in Saos-2 cells demonstrated that TNF-α stimulation markedly increased ADAMTS-2 mRNA (~ 17-fold) and protein levels (~ twofold). Promoter activity assays showed strong TNF-α–mediated activation, with the highest induction in the − 180/ + 112 region. Pharmacological inhibition experiments revealed that MEK, PI3K, JNK, and NF-κB pathways are all required for TNF-α-induced ADAMTS-2 transcription. In silico motif analysis identified STAT3 and NF-κB binding elements within the promoter, and electrophoretic mobility shift assays supported the interaction of these transcription factors with specific promoter regions.

Conclusions

This study provides the first mechanistic evidence that TNF-α regulates ADAMTS-2 expression through the coordinated activation of multiple signaling pathways and the engagement of STAT3 and NF-κB transcription factors at the promoter. These findings uncover a previously uncharacterized inflammatory regulatory axis linking TNF-α signaling to ECM remodeling and highlight ADAMTS-2 as a potential mediator of osteosarcoma progression.