Antagonizing microRNA ‐19a/b augments PTH anabolic action and restores bone mass in osteoporosis in mice

Abstract

Postmenopausal bone loss often leads to osteoporosis and fragility fractures. Bone mass can be increased by the first 34 amino acids of human parathyroid hormone (PTH), parathyroid hormone-related protein (PTHrP), or by a monoclonal antibody against sclerostin (Scl-Ab). Here, we show that PTH and Scl-Ab reduce the expression of in bone. In bones from patients with lower bone mass and from osteoporotic mice, miR-19a/b expression is elevated, suggesting an inhibitory function in bone remodeling. Indeed, antagonizing miR-19a/b in vivo increased bone mass without overt cytotoxic effects. We identified TG-interacting factor 1 (Tgif1) as the target of miR-19a/b in osteoblasts and essential for the increase in bone mass following miR-19a/b inhibition. Furthermore, antagonizing miR-19a/b augments the gain in bone mass by PTH and restores bone loss in mouse models of osteoporosis in a dual mode of action by supporting bone formation and decreasing receptor activator of NF-jB ligand (RANKL)dependent bone resorption. Thus, this study identifies novel mechanisms regulating bone remodeling, which opens opportunities for new therapeutic concepts to treat bone fragility.

Tgif1-deficiency impairs cytoskeletal architecture in osteoblasts by activating PAK3 signaling

“…Intermittent administration of PTH augments bone formation, leading to a remodeling-based increase in bone mass, bone mineral density and a consecutive decrease in fracture rate in humans ( Neer et al, 2001 ; Taipaleenmäki et al, 2022 ; Baron and Hesse, 2012 ). This anabolic function requires multiple alterations at the cellular level.…”

Dysregulation of MicroRNAs in Adult Osteogenesis Imperfecta: The miROI Study

“…[58,59] Recent studies have demonstrated that the inhibition of miR-19a/b in osteoporotic rats significantly enhances the effect of parathyroid hormone on osteoformation by relieving the inhibition on TG-interacting factor 1 and reducing RANKL-mediated resorption activity. [60] The lack of significance in the structural mutation group suggests that this mechanism is not effective, possibly triggered solely by the quantitative decrease of COL1A1.…”

“…[89,90] It is therefore relevant to consider this approach in bone diseases so our results could form the basis for in vitro and in vivo investigations in this direction especially since some animal model studies in osteoporosis seem to be promising (miR-106b, miR-19a/b). [54,60] However, the miROI study has some limitations. The limited number of patients with type 3 OI does not allow for exploring the concept of severity in this form.…”

“…[ 89,90 ] It is therefore relevant to consider this approach in bone diseases so our results could form the basis for in vitro and in vivo investigations in this direction especially since some animal model studies in osteoporosis seem to be promising (miR‐106b, miR‐19a/b). [ 54,60 ]…”

The miR-19a/Cylindromatosis Axis Regulates Pituitary Adenoma Bone Invasion by Promoting Osteoclast Differentiation

“…MicroRNAs (miRNAs) are a group of small noncoding RNAs of approximately [16][17][18][19][20] nucleotides that regulate gene expression at the post-transcriptional level [16]. Members of the miR-19 family (including miR-19a, miR-19b-1, and miR-19b-2), as members of the miR-17/92 cluster, have been identified as important oncogenic miRNAs that have been reported to be upregulated in a variety of tumors [21][22][23].…”