TNF/TNFR modulates the Traf2-Gαs axis to promote aging-related bone loss and impair PTH (1-34) efficacy

Chu Tao; Sixiong Lin; Yujia Shi; Qiuhua Yang; Weiyuan Gong; Qinnan Yan; Xuekun Fu; Donghao Gan; Peijun Zhang; Xuenong Zou; Chao Liang; Di Chen; Xiaochun Bai; Fuxin Wei; Qing Yao; Guozhi Xiao

doi:10.59717/j.xinn-med.2026.100237

The Innovation Medicine > 2026 Vol. 4 > No. 3 > 100237

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TNF/TNFR modulates the Traf2-Gαs axis to promote aging-related bone loss and impair PTH (1-34) efficacy

1.
Department of Biochemistry, Homeostatic Medicine Institute, School of Medicine, Shenzhen Key Laboratory of Cell Microenvironment, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Southern University of Science and Technology, Shenzhen 518055, China
2.
Department of Orthopaedics, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
3.
School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR 999077, China
4.
Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China
5.
Department of Biomedical Engineering, the Hong Kong Polytechnic University, Hong Kong SAR 999077, China
6.
Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Department of Spinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
7.
Research Center for Human Tissues and Organs Degeneration, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
8.
Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
9.
Department of Orthopaedics, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China
10.
These authors contributed equally

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Corresponding authors: xiaogz@sustech.edu.cn (G.X.); angela.yaoqing@gmail.com (Q.Y.)
Received Date: August 15, 2025

Accepted Date: July 09, 2026

Published Online: July 11, 2026

The Innovation Medicine 4(3), https://doi.org/10.59717/j.xinn-med.2026.100237 | Cite this article

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PUBLIC SUMMARY
1. Tumor necrosis factor (TNF) increases in aging bones and weakens bone formation.
  
  TNF reduces the effectiveness of parathyroid hormone (PTH) therapy in elderly bone.
  
  Blocking TNF signaling prevents age-related bone loss in mice.
  
  Combining TNF inhibition with PTH improves bone-building effects in aged animals.

ABSTRACT

ABSTRACT

The anti-osteoporotic effects of parathyroid hormone (PTH) analogs for patients with severe osteoporosis decrease with age; however, the underlying mechanism(s) are poorly understood. Here we provide evidence that enhanced TNF-mediated chronic inflammation during aging may play a critical role in promoting bone loss and attenuating the anabolic effects of PTH on bone in aged individuals. Specifically, we find that abolishment of TNF signaling activation by global deletion of the Tnfr1/2 genes, which encode the TNF receptors, prevents aging-related bone mass loss and improves the anabolic effects of PTH (1-34) analog to increase bone mass and bone mineral density in aged, but not young adult, mice. These effects are achieved mainly by enhancing PTH signaling in osteoblastic cells, leading to accelerated bone formation. TNF-α inhibition of PTH signaling is mediated via TRAF2, an E3 ligase. TRAF2 promotes the non-canonical K27- and K33-linked ubiquitination of Gαs, which increases Gαs protein stability but blocks Gαs activation and downstream signaling. Of clinical significance, infliximab, a TNF-α neutralizing antibody, reduces the bone loss in aged mice and improves the skeletal response to PTH. Collectively, we demonstrate a novel mechanism whereby TNF/TNFR/TRAF2 promotes aging-related bone loss and impairs the anabolic effects of PTH on bone in aged animals by inhibiting Gαs activation, and our findings suggest that modulating the TNF/TNFR signaling pathway may improve the effectiveness of PTH treatment in senile osteoporosis patients.

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Tao C., Lin S., Shi Y., et al. (2026). TNF/TNFR modulates the Traf2-Gαs axis to promote aging-related bone loss and impair PTH (1-34) efficacy. The Innovation Medicine 4:100237. https://doi.org/10.59717/j.xinn-med.2026.100237

Tao C., Lin S., Shi Y., et al. (2026). TNF/TNFR modulates the Traf2-Gαs axis to promote aging-related bone loss and impair PTH (1-34) efficacy. The Innovation Medicine 4:100237. https://doi.org/10.59717/j.xinn-med.2026.100237

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TNF/TNFR modulates the Traf2-Gαs axis to promote aging-related bone loss and impair PTH (1-34) efficacy

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