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Introduction <p>Giant cell tumor of bone (GCTB) induces overproduction of bone-resorbing osteoclasts through receptor activator of nuclear factor kappa B ligand (RANKL), leading to bone resorption and destruction. Consequently, denosumab, a neutralizing antibody against RANKL (a cytokine essential for osteoclast induction), is used to treat patients with GCTB. However, the activity of bone formation in GCTB remains poorly understood. Here, we show that GCTB antagonizes bone formation by expressing WNT5B, which inhibits bone formation.</p> Materials and methods <p>Co-culture of NCC-GCTB1-C1 (GCTB1s), a human GCTB cell line, with human adipose-derived stem cells (ADSCs) was performed with osteoblast induction medium. To identify the inhibitors of osteoblast differentiation, we reanalyzed the single-cell RNA sequencing data that was previously published. In addition, we performed spatial transcriptome analysis (Visium) against the section of paraffin block of GCTB. The targeted protein was knocked out using CRISPR/Cas9 and co-culture was performed.</p> Results <p>Co-culture of GCTB1s with ADSCs significantly inhibited mineralization of ADSCs. Reanalysis of single-cell RNA sequencing data indicated that GCTB tumors express <i>WNT5B,</i> and we observed that GCTB1s express <i>WNT5B</i>. We then knocked out <i>WNT5B</i> in GCTB1s using CRISPR/Cas9 and co-cultured them with ADSCs and observed significant rescue of mineralization in ADSCs relative to ADSCs cultured with GCTB1s expressing <i>WNT5B</i>. We also show that ADSC supernatants induce mineralization of GCTB1s.</p> Conclusion <p>These studies indicate that GCTB not only induces osteoclasts, but also possesses activity that inhibits bone formation.</p>

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Giant cell tumor of bone inhibits osteoblastogenesis via WNT5B

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月23日

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  • Masaki Shimada,
  • Tomonori Tsuyama,
  • Naoto Yoshimura,
  • Makoto Tateyama,
  • Hideto Matsunaga,
  • Fuka Homma,
  • Kasumi Dainobu,
  • Xiao Tian,
  • Shu Takata,
  • Kosei Takata,
  • Shuntaro Tanimura,
  • Yuto Shibata,
  • Kazuya Maeda,
  • Junki Kawakami,
  • Takahiro Arima,
  • Tatsuki Karasugi,
  • Takuya Tokunaga,
  • Hiro Sato,
  • Tetsuro Masuda,
  • Satoshi Hisanaga,
  • Yuki Kai,
  • Soichiro Karata,
  • Hikaru Goshogawa,
  • Rui Tajiri,
  • Hibiki Yamada,
  • Yusuke Uehara,
  • Takayuki Nakamura,
  • Masaki Yugami,
  • Kazuki Sugimoto,
  • Ryuji Yonemitsu,
  • Hironori Tanoue,
  • Kazuya Yamagata,
  • Takeshi Miyamoto

摘要

Introduction

Giant cell tumor of bone (GCTB) induces overproduction of bone-resorbing osteoclasts through receptor activator of nuclear factor kappa B ligand (RANKL), leading to bone resorption and destruction. Consequently, denosumab, a neutralizing antibody against RANKL (a cytokine essential for osteoclast induction), is used to treat patients with GCTB. However, the activity of bone formation in GCTB remains poorly understood. Here, we show that GCTB antagonizes bone formation by expressing WNT5B, which inhibits bone formation.

Materials and methods

Co-culture of NCC-GCTB1-C1 (GCTB1s), a human GCTB cell line, with human adipose-derived stem cells (ADSCs) was performed with osteoblast induction medium. To identify the inhibitors of osteoblast differentiation, we reanalyzed the single-cell RNA sequencing data that was previously published. In addition, we performed spatial transcriptome analysis (Visium) against the section of paraffin block of GCTB. The targeted protein was knocked out using CRISPR/Cas9 and co-culture was performed.

Results

Co-culture of GCTB1s with ADSCs significantly inhibited mineralization of ADSCs. Reanalysis of single-cell RNA sequencing data indicated that GCTB tumors express WNT5B, and we observed that GCTB1s express WNT5B. We then knocked out WNT5B in GCTB1s using CRISPR/Cas9 and co-cultured them with ADSCs and observed significant rescue of mineralization in ADSCs relative to ADSCs cultured with GCTB1s expressing WNT5B. We also show that ADSC supernatants induce mineralization of GCTB1s.

Conclusion

These studies indicate that GCTB not only induces osteoclasts, but also possesses activity that inhibits bone formation.