2. Academic Validation
  3. Glia maturation factor beta deficiency protects against diabetic osteoporosis by suppressing osteoclast hyperactivity

Glia maturation factor beta deficiency protects against diabetic osteoporosis by suppressing osteoclast hyperactivity

  • Exp Mol Med. 2023 May 1. doi: 10.1038/s12276-023-00980-8.
Si Shi # 1,  Huijie Gu # 2,  Jinyuan Xu 1,  Wan Sun 1,  Caiyin Liu 1,  Tong Zhu 1,  Juan Wang 1,  Furong Gao 1,  Jieping Zhang 1,  Qingjian Ou 1,  Caixia Jin 1,  Jingying Xu 1,  Hao Chen 3,  Jiao Li 1,  Guotong Xu 4 5,  Haibin Tian 6 7,  Lixia Lu 8 9
Affiliations

Affiliations

  • 1 Department of Ophthalmology of the Shanghai Tongji Hospital Affiliated with Tongji University, School of Medicine, and Tongji Eye Institute, 389 Xinchun Road, Shanghai, 200065, PR China.
  • 2 Department of Orthopedics, Minhang Hospital, Fudan University, 170 Xinsong Road, Shanghai, 201199, PR China.
  • 3 Department of Ophthalmology of Ten People Hospital Affiliated with Tongji University, School of Medicine, Shanghai, 200072, PR China.
  • 4 Department of Ophthalmology of the Shanghai Tongji Hospital Affiliated with Tongji University, School of Medicine, and Tongji Eye Institute, 389 Xinchun Road, Shanghai, 200065, PR China. gtxu@tongji.edu.cn.
  • 5 Department of Pharmacology, Tongji University School of Medicine, Shanghai, PR China. gtxu@tongji.edu.cn.
  • 6 Department of Ophthalmology of the Shanghai Tongji Hospital Affiliated with Tongji University, School of Medicine, and Tongji Eye Institute, 389 Xinchun Road, Shanghai, 200065, PR China. tianh@tongji.edu.cn.
  • 7 Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, 1239 Siping Road, Shanghai, 200092, PR China. tianh@tongji.edu.cn.
  • 8 Department of Ophthalmology of the Shanghai Tongji Hospital Affiliated with Tongji University, School of Medicine, and Tongji Eye Institute, 389 Xinchun Road, Shanghai, 200065, PR China. 98738@tongji.edu.cn.
  • 9 Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, 1239 Siping Road, Shanghai, 200092, PR China. 98738@tongji.edu.cn.
  • # Contributed equally.
PMID: 37121966 DOI: 10.1038/s12276-023-00980-8
Abstract

Excessive osteoclast activation, which depends on dramatic changes in actin dynamics, causes osteoporosis (OP). The molecular mechanism of osteoclast activation in OP related to type 1 diabetes (T1D) remains unclear. Glia maturation factor beta (GMFB) is considered a growth and differentiation factor for both glia and neurons. Here, we demonstrated that Gmfb deficiency effectively ameliorated the phenotype of T1D-OP in rats by inhibiting osteoclast hyperactivity. In vitro assays showed that GMFB participated in osteoclast activation rather than proliferation. Gmfb deficiency did not affect osteoclast sealing zone (SZ) formation but effectively decreased the SZ area by decreasing actin depolymerization. When GMFB was overexpressed in Gmfb-deficient osteoclasts, the size of the SZ area was enlarged in a dose-dependent manner. Moreover, decreased actin depolymerization led to a decrease in nuclear G-actin, which activated MKL1/SRF-dependent gene transcription. We found that pro-osteoclastogenic factors (Mmp9 and Mmp14) were downregulated, while anti-osteoclastogenic factors (CFTR and Fhl2) were upregulated in Gmfb KO osteoclasts. A GMFB inhibitor, DS-30, targeting the binding site of GMFB and Arp2/3, was obtained. Biocore analysis revealed a high affinity between DS-30 and GMFB in a dose-dependent manner. As expected, DS-30 strongly suppressed osteoclast hyperactivity in vivo and in vitro. In conclusion, our work identified a new therapeutic strategy for T1D-OP treatment. The discovery of GMFB inhibitors will contribute to translational research on T1D-OP.

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