Inhibition of miR-29 Activity in the Myeloid Lineage Increases Response to Calcitonin and Trabecular Bone Volume in Mice.

Abstract

The miR-29-3p family (miR-29a, miR-29b, miR-29c) of microRNAs is increased during receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis. In vivo, activation of a miR-29-3p tough decoy inhibitor in Cre recombinase under the control of the lysozyme 2 promoter-expressing cells (myeloid lineage) resulted in mice displaying enhanced trabecular and cortical bone volume because of decreased bone resorption. Calcitonin receptor (Calcr) is a miR-29 target that negatively regulates bone resorption. CALCR was significantly increased in RANKL-treated miR-29-decoy osteoclasts, and these cells were more responsive to the inhibitory effect of calcitonin on osteoclast formation. Further, cathepsin K (Ctsk), which is critical for resorption, was decreased in miR-29-decoy cells. CALCR is a Gs-coupled receptor and its activation raises cAMP levels. In turn, cAMP suppresses cathepsin K, and cAMP levels were increased in miR-29-decoy cells. siRNA-mediated knock-down of Calcr in miR-29 decoy osteoclasts allowed recovery of cathepsin K levels in these cells. Overall, using a novel knockin tough decoy mouse model, we identified a new role for miR-29-3p in bone homeostasis. In RANKL-driven osteoclastogenesis, as seen in normal bone remodeling, miR-29-3p promotes resorption. Consequently, inhibition of miR-29-3p activity in the myeloid lineage leads to increased trabecular and cortical bone. Further, this study documents an interrelationship between CALCR and CTSK in osteoclastic bone resorption, which is modulated by miR-29-3p.

• Authors: Bongjin Shin, Henry C Hrdlicka, Anne M Delany, Sun-Kyeong Lee
• Journal: Endocrinology (Endocrinology) Vol. 162 Issue 10 (10 01 2021) ISSN: 1945-7170 [Electronic] United States
• PMID: 34192317 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Actins
• MIRN29 microRNA, mouse
• MicroRNAs
• Protein Precursors
• RANK Ligand
• Tnfsf11 protein, mouse
• preprocalcitonin
• Calcitonin
• Cre recombinase
• Integrases
• Muramidase
• Cathepsin K

Topics

• Actins (metabolism)
• Alleles
• Animals
• Bone Resorption
• Bone and Bones (metabolism)
• Calcitonin (metabolism)
• Cancellous Bone (drug effects)
• Cathepsin K (metabolism)
• Cell Differentiation (drug effects)
• Cell Lineage
• Female
• Homeostasis
• Integrases
• Male
• Mice
• Mice, Inbred C57BL
• MicroRNAs (antagonists & inhibitors, genetics)
• Muramidase (chemistry)
• Myeloid Cells (metabolism)
• Osteoclasts (drug effects, metabolism)
• Osteogenesis (drug effects)
• Protein Precursors
• RANK Ligand (metabolism)
• X-Ray Microtomography