Background/Purpose: Micro RNAs (miRNAs) play a crucial role in the regulation of bone metabolism. MiR-146a, an important anti-inflammatory miRNA, was found to negatively impact osteogenesis and bone regeneration in vitro, by controlling the differentiation of mesenchymal stem cells. But to date the role of miR-146a in bone remodelling, its influence on bone stability and development of osteoporosis is not known.

Methods: Systemic bone, tibiae and femur, of wt, miR-146a^-/- and miR- 146a^-/- TRAF6^+/- animals was assessed histologically and via µCT analysis, over a period of 3 to 18 months of age. Serum cytokine levels were analysed by Elisa. MRNA expression levels in bone were analysed by qPCR. To induce osteoporosis, ovariectomy (OVX) induced bone loss was performed.

Results: When we analysed bone volume of long bones histologically as well as with µCT analysis we detected significantly increased trabecular as well as cortical bone mass in miR-146a deficient compared to wt animals, starting at an age of 6 months. Dose reduction of TRAF6, a main target of miR-146a, using miR-146a^-/- TRAF6^+/- animals could not change the observed bone phenotype. Analysis of serum in aged miR-146a deficient animals displayed elevated activity of bone resorbing osteoclasts as amounts of CTX I in miR-146a^-/- mice were significantly increased compared to wt animals. Q-PCR analysis of important osteoclast as well as osteoblast marker genes in bones ex vivo displayed elevated expression of signature molecules of both cell types in aged miR-146a deficient mice, suggesting a regulatory role of miR-146a in both cell types. Moreover, expression level of Wnt5a, a known target of miR-146a, influencing bone forming as well as bone resorbing cells, was strongly elevated in miR-146a^-/- bones, possibly responsible for this deregulated bone growth. When we induced osteoporosis using the OVX disease model, histological analysis of long bones showed significant trabecular bone loss in ovariectomized wt mice. In contrast, we could not detect trabecular bone loss in ovariectomized miR-146a knock out animals, suggesting that loss of miR-146a deficiency protects bone loss induced by estrogen deficiency.

Conclusion: MiR-146a seems to control bone turnover and miR-146a deficient mice accrue bone over time. Moreover this miRNA has a negative influence on bone loss occurring during oestrogen loss induced osteoporosis. Therefore, miR-146a could be possibly used as a therapeutic target in the treatment of osteoporosis. 

ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-emerging-regulatory-function-of-microrna146a-in-bone-biology-and-osteoporosis/