Sclerostin vaccination mitigates estrogen deficiency induction of bone mass loss and microstructure deterioration

Feng Sheng Wang, Re Wen Wu, Wei Shiung Lain, Tsai Chen Tsai, Yu Shan Chen, Yi Chih Sun, Huei Jing Ke, Jui Chen Li, Jaulang Hwang, Jih Yang Ko

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Sclerostin (SOST) is a Wnt signaling inhibitor detrimental to osteogenic differentiation and bone mineral acquisition. While control of SOST action delays the pathogenesis of skeletal disorders, the effects of SOST vaccination on the estrogen deficiency-induced bone deterioration remain elusive. In this study, we generated a SOST-Fc fusion protein which was composed of a SOST peptide Pro-Asn-Ala-Ile-Gly along with an IgG Fc fragment. SOST-Fc vaccination increased serum anti-SOST antibody levels and reduced serum SOST concentrations in mice. In vitro, anti-SOST serum attenuated the SOST-induced inhibition of osteogenic gene expression in osteoblast cultures. Administration with SOST-Fc increased serum levels of bone formation marker osteocalcin and alleviated the ovariectomy escalation of serum resorption markers CTX-1 and TRAP5b concentrations. It remarkably lessened the estrogen deficiency-mediated deterioration of bone mineral density, morphometric characteristics of trabecular bone, and mechanical strength of femurs and lumbar spines. The SOST-Fc-treated skeletal tissue exhibited moderate responses to the adverse actions of ovariectomy to bone mineral accretion, osteoclast surface, trabecular separation, and fatty marrow histopathology. SOST-Fc treatment increased serum osteoclast-inhibitory factor osteoprotegrin levels in conjunction with strong Wnt3a, β-catenin, and TCF4 immunostaining in osteoblasts, whereas it weakened the estrogen deficiency enhancement of osteoclast-promoting factor receptor activator of nuclear factor-κB ligand. Taken together, blockade of SOST action by SOST-Fc vaccination sustains Wnt signaling, which harmonizes bone mineral accretion and resorption reactions and thereby ameliorates ovariectomy-induced bone loss. This study highlights SOST-Fc fusion protein as a new molecular therapeutic potential for preventing from osteoporotic disorders.

Original languageEnglish
Pages (from-to)24-34
Number of pages11
JournalBone
Volume112
DOIs
Publication statusPublished - Jul 1 2018
Externally publishedYes

Keywords

  • Estrogen deficiency
  • Fc fusion protein
  • Osteoporosis
  • Sclerostin
  • Vaccination

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

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  • Cite this

    Wang, F. S., Wu, R. W., Lain, W. S., Tsai, T. C., Chen, Y. S., Sun, Y. C., Ke, H. J., Li, J. C., Hwang, J., & Ko, J. Y. (2018). Sclerostin vaccination mitigates estrogen deficiency induction of bone mass loss and microstructure deterioration. Bone, 112, 24-34. https://doi.org/10.1016/j.bone.2018.04.007