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Background <p>This study investigated the role and underlying mechanism of large tumor suppressor 1/2 (LATS1/2), a core kinase in the Hippo pathway, in inhibiting osteoclastic differentiation and ameliorating ovariectomy (OVX)-induced osteoporosis in rats through the RANKL-dependent Hippo–YAP/TAZ signaling pathway both in vivo and in vitro.</p> Methods <p>Under stimulation by receptor activator of nuclear factor-κB ligand (RANKL), small interfering RNA (siRNA) was used to suppress the expression of LATS1/2 and YAP. The levels of osteoclast-related genes and proteins, as well as YAP pathway proteins, were evaluated in RAW264.7 cells and bone marrow-derived macrophages (BMMs) via quantitative reverse transcription polymerase chain reaction and Western blot analysis. Cell viability and osteoclast formation potential were measured via the Cell Counting Kit-8 assay and tartrate-resistant acid phosphatase (TRAP) staining, respectively. Osteoclasts and filamentous actin were stained with TRAP and phalloidin to characterize cell morphology. Furthermore, to research the role of the Hippo/YAP pathway, we used siRNA to knock down LATS1/2 and examined its effect on RANKL-mediated osteoclast differentiation. In addition, we constructed an OVX-induced osteoporosis model in 8-week-old female Sprague‒Dawley rats, treated them with a LATS1/2 inhibitor for 4&#xa0;weeks at 12&#xa0;weeks after surgery, and evaluated the remission of osteoporosis by micro-CT and histological methods with a LATS1/2 inhibitor.</p> Results <p>After LATS1/2 was silenced or inhibited in BMMs and RAW264.7 cells, YAP was significantly upregulated and YAP phosphorylation and osteoclast function were inhibited. By interfering with YAP expression, the Hippo/YAP pathway inhibited osteoclast differentiation in BMMs. In vivo, injection of LATS1/2 inhibitor alleviated osteoporosis in ovariectomized rats.</p> Conclusion <p>Our findings indicate that the inhibition of LATS1/2 considerably suppresses osteoclast differentiation and alleviates OVX-induced osteoporosis in rats. Additionally, our results show that LATS1/2 inhibitors are important for the differentiation of osteoclasts and highlight the possible therapeutic value of LATS1/2 inhibitors.</p>

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LATS1/2 Inhibitor Attenuates Osteoclast Differentiation via Hippo–YAP/TAZ Signaling Pathway and Alleviates Osteoporosis in Ovariectomized Rats

  • 期刊论文

  • 发表日期：

    2026年4月1日

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  • Si-hui Chen,
  • Yi Jiang,
  • Guo-qing Xie,
  • Zhi-hao Fang,
  • Bu-yi Zhang,
  • Chun-yu Jiang,
  • Jin-yu Zhu

摘要

Background

This study investigated the role and underlying mechanism of large tumor suppressor 1/2 (LATS1/2), a core kinase in the Hippo pathway, in inhibiting osteoclastic differentiation and ameliorating ovariectomy (OVX)-induced osteoporosis in rats through the RANKL-dependent Hippo–YAP/TAZ signaling pathway both in vivo and in vitro.

Methods

Under stimulation by receptor activator of nuclear factor-κB ligand (RANKL), small interfering RNA (siRNA) was used to suppress the expression of LATS1/2 and YAP. The levels of osteoclast-related genes and proteins, as well as YAP pathway proteins, were evaluated in RAW264.7 cells and bone marrow-derived macrophages (BMMs) via quantitative reverse transcription polymerase chain reaction and Western blot analysis. Cell viability and osteoclast formation potential were measured via the Cell Counting Kit-8 assay and tartrate-resistant acid phosphatase (TRAP) staining, respectively. Osteoclasts and filamentous actin were stained with TRAP and phalloidin to characterize cell morphology. Furthermore, to research the role of the Hippo/YAP pathway, we used siRNA to knock down LATS1/2 and examined its effect on RANKL-mediated osteoclast differentiation. In addition, we constructed an OVX-induced osteoporosis model in 8-week-old female Sprague‒Dawley rats, treated them with a LATS1/2 inhibitor for 4 weeks at 12 weeks after surgery, and evaluated the remission of osteoporosis by micro-CT and histological methods with a LATS1/2 inhibitor.

Results

After LATS1/2 was silenced or inhibited in BMMs and RAW264.7 cells, YAP was significantly upregulated and YAP phosphorylation and osteoclast function were inhibited. By interfering with YAP expression, the Hippo/YAP pathway inhibited osteoclast differentiation in BMMs. In vivo, injection of LATS1/2 inhibitor alleviated osteoporosis in ovariectomized rats.

Conclusion

Our findings indicate that the inhibition of LATS1/2 considerably suppresses osteoclast differentiation and alleviates OVX-induced osteoporosis in rats. Additionally, our results show that LATS1/2 inhibitors are important for the differentiation of osteoclasts and highlight the possible therapeutic value of LATS1/2 inhibitors.