2. Academic Validation
  3. FSTL1 promotes osteoclast differentiation and Accelerates periprosthetic osteolysis via PP2A Cα-Mediated activation of the JNK signaling pathway

FSTL1 promotes osteoclast differentiation and Accelerates periprosthetic osteolysis via PP2A Cα-Mediated activation of the JNK signaling pathway

  • Biochem Pharmacol. 2025 Dec;242(Pt 4):117450. doi: 10.1016/j.bcp.2025.117450.
Maoyuan Li 1,  Liangliang Wang 2,  Feng Lu 1,  Shishuo Li 3,  Yunyuan Yu 4,  Huiqun Hu 5,  Guangrong Yin 2,  Chao Xu 2,  Yimin Liu 1,  Yuji Wang 6
Affiliations

Affiliations

  • 1 Department of Orthopedics, The Third Affiliated Hospital of Nanjing Medical University (Changzhou No. 2 People's Hospital), Changzhou, Jiangsu Province 213003, China; Nanjing Medical University, Nanjing 210000, China.
  • 2 Department of Orthopedics, The Third Affiliated Hospital of Nanjing Medical University (Changzhou No. 2 People's Hospital), Changzhou, Jiangsu Province 213003, China.
  • 3 Department of Orthopedics, The Third Affiliated Hospital of Nanjing Medical University (Changzhou No. 2 People's Hospital), Changzhou, Jiangsu Province 213003, China; Graduate School of Dalian Medical University, Dalian, Liaoning Province 116044, China.
  • 4 Articular Orthopaedics, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China.
  • 5 Department of Thoracic Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou 310022, China; Department of Infectious Diseases, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
  • 6 Department of Orthopedics, The Third Affiliated Hospital of Nanjing Medical University (Changzhou No. 2 People's Hospital), Changzhou, Jiangsu Province 213003, China; Department of Orthopedics, The Third Affiliated Hospital of Gansu University of Chinese Medicine, 222 Silong Road, Baiyin 730900, China; Department of Orthopedic Surgery and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA. Electronic address: yujiwang1036@njmu.edu.cn.
PMID: 41130306 DOI: 10.1016/j.bcp.2025.117450
Abstract

Periprosthetic osteolysis (PPO) is a common cause of arthroplasty failure, characterized by chronic inflammation and osteoclast differentiation, ultimately necessitating revision surgery. Follistatin-like 1 (FSTL1) is a critical modulator of inflammation and has an important function in different inflammatory disorders, including osteoarthritis and rheumatoid arthritis. This research examines the function of FSTL1 in PPO and elucidates the underlying mechanisms. In human aseptic loosening periprosthetic interface membranes and titanium (Ti) nanoparticle-induced calvarial osteolysis models, FSTL1 expression was markedly elevated. The administration of recombinant FSTL1 (rFSTL1) to calvariae significantly exacerbated Ti nanoparticle-induced bone resorption at osteolytic sites and increased both osteoclastogenesis and pro-inflammatory factor expression. However, the knockdown of FSTL1 using adeno-associated virus (AAV) effectively mitigated calvarial osteolysis and decreased both osteoclastogenesis and pro-inflammatory factor expression. Mechanistically, FSTL1 facilitates osteoclast differentiation and bone resorption through the upregulation of protein Phosphatase 2A C subunit alpha (PP2A Cα) expression, which enhances the RANKL-induced activation of the JNK signaling pathway, thereby increasing the expression of downstream transcription factors cellular proto-oncogene Fos (c-Fos) and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1). Furthermore, FSTL1 intensifies the inflammatory response at osteolytic sites, also contributing to the progression of osteolysis. Our findings indicate that FSTL1 may represent a promising therapeutic target for the treatment of periprosthetic osteolysis.

Keywords

FSTL1; Osteoclast differentiation; PP2A; Periprosthetic osteolysis; Ti nanoparticle.

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