2. Academic Validation
  3. Activating transcriptional coactivator with PDZ-binding motif by (R)-PFI-2 attenuates osteoclastogenesis and prevents ovariectomized-induced osteoporosis

Activating transcriptional coactivator with PDZ-binding motif by (R)-PFI-2 attenuates osteoclastogenesis and prevents ovariectomized-induced osteoporosis

  • Biochem Pharmacol. 2023 Dec 2:115964. doi: 10.1016/j.bcp.2023.115964.
Rongjian Xu 1,  Xuewen Liu 1,  Yufeng Zhang 1,  Kelei Wang 2,  Zhuolin Chen 2,  Jiewen Zheng 2,  Tan Zhang 2,  Peijian Tong 3,  Yu Qian 4,  Wanlei Yang 5
Affiliations

Affiliations

  • 1 The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, China; Department of Orthopedics, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, Zhejiang Province 312000, China.
  • 2 Department of Orthopedics, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, Zhejiang Province 312000, China.
  • 3 Department of Orthopedics Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310006, China. Electronic address: tongpeijian@163.com.
  • 4 The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, China; Department of Orthopedics Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310006, China. Electronic address: doctor120@hotmail.com.
  • 5 Department of Orthopedics Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310006, China. Electronic address: 20223010@zcmu.edu.cn.
PMID: 38049011 DOI: 10.1016/j.bcp.2023.115964
Abstract

Excessive osteoclast activation is a leading cause of osteoporosis. Therefore, identifying molecular targets and relevant pharmaceuticals that inhibit osteoclastogenesis is of substantial clinical importance. Prior research has indicated that transcriptional coactivator with PDZ-binding motif (TAZ) impedes the process of osteoclastogenesis by engaging the nuclear factor (NF)-κB signaling pathway, thereby suggesting TAZ activation as a potential therapeutic approach to treat osteoporosis. (R)-PFI-2 is a novel selective inhibitor of SETD7 methyltransferase activity, which prevents the nuclear translocation of YAP, a homolog of TAZ. Therefore, we hypothesized that (R)-PFI-2 could be an effective therapeutic agent in the treatment of osteoporosis. To test this hypothesis and explore the underlying mechanism, we first examined the impact of (R)-PFI-2 on osteoclastogenesis in bone marrow macrophages (BMMs) in vitro. (R)-PFI-2 treatment inhibited TAZ phosphorylation induced by NF-κB, thereby enhancing its nuclear localization, protein expression, and activation in BMMs. Moreover, (R)-PFI-2-induced TAZ activation inhibited osteoclast formation in a dose-dependent manner, which involved inhibition of osteoclastogenesis through the TAZ and downstream NF-κB pathways. Furthermore, (R)-PFI-2 inhibited osteoclastogenesis and prevented ovariectomy-induced bone loss in vivo in a mouse model. Overall, our findings suggest that TAZ activation by (R)-PFI-2 inhibits osteoclastogenesis and prevents osteoporosis, indicating an effective strategy for treating osteoclast-induced osteoporosis.

Keywords

(R)-PFI-2; NF-κB; Osteoclastogenesis; Osteoporosis; Transcriptional coactivator with PDZ-binding motif (TAZ).

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