2. Academic Validation
  3. Inhibition of Protein Disulfide Isomerase Attenuates Osteoclast Differentiation and Function via the Readjustment of Cellular Redox State in Postmenopausal Osteoporosis

Inhibition of Protein Disulfide Isomerase Attenuates Osteoclast Differentiation and Function via the Readjustment of Cellular Redox State in Postmenopausal Osteoporosis

  • Inflammation. 2023 Dec 6. doi: 10.1007/s10753-023-01933-z.
Yi Wang # 1 2,  Tao Yuan # 3,  Haojue Wang 3,  Qi Meng 3,  Haoyang Li 3,  Changgong Feng 1 2,  Ziqing Li 4 5,  Shui Sun 6 7 8
Affiliations

Affiliations

  • 1 Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
  • 2 Orthopaedic Research Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China.
  • 3 Department of Joint Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
  • 4 Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China. liziqing@sdfmu.edu.cn.
  • 5 Orthopaedic Research Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China. liziqing@sdfmu.edu.cn.
  • 6 Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China. sunshui@sdfmu.edu.cn.
  • 7 Department of Joint Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China. sunshui@sdfmu.edu.cn.
  • 8 Orthopaedic Research Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China. sunshui@sdfmu.edu.cn.
  • # Contributed equally.
PMID: 38055120 DOI: 10.1007/s10753-023-01933-z
Abstract

Due to the accumulation of Reactive Oxygen Species (ROS) and heightened activity of osteoclasts, postmenopausal osteoporosis could cause severe pathological bone destruction. Protein disulfide isomerase (PDI), an endoplasmic prototypic thiol isomerase, plays a central role in affecting cellular redox state. To test whether suppression of PDI could inhibit osteoclastogenesis through cellular redox regulation, bioinformatics network analysis was performed on the causative genes, followed by biological validation on the osteoclastogenesis in vitro and ovariectomy (OVX) mice model in vivo. The analysis identified PDI as one of gene targets for postmenopausal osteoporosis, which was positively expressed during osteoclastogenesis. Therefore, PDI expression inhibitor and chaperone activity inhibitor were used to verify the effects of PDI inhibitors on osteoclastogenesis. Results demonstrated that PDI inhibitors could reduce osteoclast number and inhibit resorption function via suppression on osteoclast marker genes. The mechanisms behind the scenes were the PDI inhibitors-caused intracellular ROS reduction via enhancement of the antioxidant system. Micro-CT and histological results indicated PDI inhibitors could effectively alleviate or even prevent bone loss in OVX mice. In conclusion, our findings unveiled the suppressive effects of PDI inhibitors on osteoclastogenesis by reducing intracellular ROS, providing new therapeutic options for postmenopausal osteoporosis.

Keywords

osteoclast; postmenopausal osteoporosis; protein disulfide isomerase (PDI); reactive oxygen species (ROS).

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