MicroRNA-29a Counteracts Glucocorticoid Induction of Bone Loss through Repressing TNFSF13b Modulation of Osteoclastogenesis

Abstract

Glucocorticoid excess escalates osteoclastic resorption, accelerating bone mass loss and microarchitecture damage, which ramps up osteoporosis development. MicroRNA-29a (miR-29a) regulates osteoblast and chondrocyte function; however, the action of miR-29a to osteoclastic activity in the glucocorticoid-induced osteoporotic bone remains elusive. In this study, we showed that transgenic mice overexpressing an miR-29a precursor driven by phosphoglycerate kinase exhibited a minor response to glucocorticoid-mediated bone mineral density loss, cortical bone porosity and overproduction of serum resorption markers C-teleopeptide of type I collagen and tartrate-resistant acid phosphatase 5b levels. miR-29a overexpression compromised trabecular bone erosion and excessive osteoclast number histopathology in glucocorticoid-treated skeletal tissue. Ex vivo, the glucocorticoid-provoked osteoblast formation and osteoclastogenic markers (NFATc1, MMP9, V-ATPase, carbonic anhydrase II and cathepsin K) along with F-actin ring development and pit formation of primary bone-marrow macrophages were downregulated in miR-29a transgenic mice. Mechanistically, tumor necrosis factor superfamily member 13b (TNFSF13b) participated in the glucocorticoid-induced osteoclast formation. miR-29a decreased the suppressor of cytokine signaling 2 (SOCS2) enrichment in the TNFSF13b promoter and downregulated the cytokine production. In vitro, forced miR-29a expression and SOCS2 knockdown attenuated the glucocorticoid-induced TNFSF13b expression in osteoblasts. miR-29a wards off glucocorticoid-mediated excessive bone resorption by repressing the TNFSF13b modulation of osteoclastic activity. This study sheds new light onto the immune-regulatory actions of miR-29a protection against glucocorticoid-mediated osteoporosis.

BMSC-Derived Exosomal miR-29a Promotes Angiogenesis and Osteogenesis

“…However, miR-29a-loaded BMSCs-Exos may have direct effects on osteogenesis and/or osteoclastogenesis. Recent studies reported that microRNA-29a can repress osteoclastogenesis to counteract glucocorticoid-induced bone loss ( Wu et al, 2019 ). Lian et al (2019) found that miR-29a regulates PCAF-mediated RANKL and CXCL12 to repress osteoclast formation.…”

The role of miR‐29 family in disease

“…GC treatment reduces miR‐29a but not miR‐29b or miR‐29c expression in rat bone and miR‐29a overexpression promotes Runx2 expression and reduces the ability of GCs to inhibit osteoblast differentiation, BMD, and trabecular bone volume 113 . miR‐29a overexpression in mice weakened GCs ability to promote RANKL expression, osteoclast differentiation, and bone erosion, independent of altered OPG expression 110,137 . The mechanisms by which miR‐29a protects the skeleton from GCs may involve miR‐29a inhibiting GC‐induced DKK‐1 expression, which would result in increased Wnt/β‐catenin signaling and osteoblast differentiation 113 .…”

“…The mechanisms by which miR‐29a protects the skeleton from GCs may involve miR‐29a inhibiting GC‐induced DKK‐1 expression, which would result in increased Wnt/β‐catenin signaling and osteoblast differentiation 113 . Alternatively, miR‐29a may delay or inhibit GC induced bone resorption by repressing tumor necrosis factor superfamily 13b expression, which supports osteoclast differentiation and maturation 137 . In conclusion, the consensus across a variety of published studies is that miR‐29s inhibit osteoclast differentiation; this may make it an attractive target to reduce bone resorption in osteoporosis and other skeletal disorders with excessive osteoclastic bone resorption.…”

The Emerging Role of MicroRNAs in NAFLD: Highlight of MicroRNA-29a in Modulating Oxidative Stress, Inflammation, and Beyond

“…In 2019, Chen et al reported that ox-LDL/CD36 signaling in macrophage links dysregulated FA metabolism and oxidative stress from the mitochondria, which drove chronic inflammation in the atherosclerosis model [122]. Our group also discovered that miR-29a protects against glucocorticoid-mediated osteoporosis by suppressing the activity of osteoclasts and differentiating from macrophages [128], thus supporting its role in regulating immune cell activity. As a result, CD36 may play a role in linking FA metabolism with mitochondrial oxidative stress and inflammation, as well as be a promising target for reversing hepatic dysfunction in NAFLD.…”