The role of nitric oxide in the mechanical repression of RANKL in bone stromal cells

Jill Rahnert, Xian Fan, Natasha Case, Tamara C. Murphy, Francesco Grassi, Buer Sen, Janet Rubin

Research output: Contribution to journalArticlepeer-review

Abstract

Both mechanical loading and nitric oxide (NO) have positive influences on bone mass. NO production is induced by mechanical strain via upregulation of eNOS mRNA and protein, the predominant NOS in adult bone. At the same time, strain causes decreased expression of RANKL, a factor critical for osteoclastogenesis. In this study, we harvested primary stromal cells from wild-type (WT) and eNOS(-/-) mice to test whether induction of NO by mechanical strain was necessary for transducing mechanical inhibition of RANKL. We found that strain inhibition of RANKL expression was prevented by NOS inhibitors (L-NAME and L-NMMA) in WT stromal cells. Surprisingly, stromal cells from eNOS(-/-) mice showed significant mechanical repression of RANKL expression (p <0.05). Mechanical strain still increased NO production in the absence of eNOS, and was abolished by SMTC, a specific nNOS inhibitor. nNOS mRNA and protein expression were increased by strain in eNOS(-/-) but not in WT cells, revealing that nNOS was mechanically sensitive. When NO synthesis was blocked with either SMTC or siRNA targeting nNOS in eNOS(-/-) cells however, strain still was able to suppress RANKL expression by 34%. This indicated that strain suppression of RANKL can also occur through non-NO dependent pathways. While our results confirm the importance of NO in the mechanical control of skeletal remodeling, they also suggest alternative signaling pathways by which mechanical force can produce anti-catabolic effects on the skeleton.

Original languageEnglish
Pages (from-to)48-54
Number of pages7
JournalBone
Volume43
Issue number1
DOIs
Publication statusPublished - Jul 2008

Keywords

  • Bone remodeling
  • eNOS
  • Mechanical strain
  • nNOS
  • RANKL

ASJC Scopus subject areas

  • Physiology
  • Hematology

Fingerprint

Dive into the research topics of 'The role of nitric oxide in the mechanical repression of RANKL in bone stromal cells'. Together they form a unique fingerprint.

Cite this