Silencing of lncRNA AK045490 Promotes Osteoblast Differentiation and Bone Formation via β-Catenin/TCF1/Runx2 Signaling Axis

Abstract

Osteoporosis, a disease characterized by both loss of bone mass and structural deterioration of bone, is the most common reason for a broken bone among the elderly. It is known that the attenuated differentiation ability of osteogenic cells has been regarded as one of the greatest contributors to age-related bone formation reduction. However, the effects of current therapies are still unsatisfactory. In this study we identify a novel long noncoding RNA AK045490 which is correlated with osteogenic differentiation and enriched in skeletal tissues of mice. In vitro analysis of bone-derived mesenchymal stem cells (BMSCs) showed that AK045490 inhibited osteoblast differentiation. In vivo inhibition of AK045490 by its small interfering RNA rescued bone formation in ovariectomized osteoporosis mice model. Mechanistically, AK045490 inhibited the nuclear translocation of β-catenin and downregulated the expression of TCF1, LEF1, and Runx2. The results suggest that Lnc-AK045490 suppresses β-catenin/TCF1/Runx2 signaling and inhibits osteoblast differentiation and bone formation, providing a novel mechanism of osteogenic differentiation and a potential drug target for osteoporosis.

The roles of miRNA, lncRNA and circRNA in the development of osteoporosis

“…Downregulation of lncRNA H19 reduced the expression level of Dkk4, thereby inhibiting the Wnt/β-catenin signaling pathway and negatively regulating osteogenic differentiation [53]. lnc-AK045490, which is enriched in skeletal tissues, inhibited osteoblast differentiation and bone formation by inhibiting nuclear translocation of β-catenin and downregulating the expression of TCF1, LEF1, and Runx2 [54]. Similarly, lnc-AK016739 inhibited osteogenic differentiation and bone formation because it could inhibit the expression and activity of osteoblastic transcription factors [55].…”

The Involvement of Long Non-Coding RNAs in Bone

“…AK045490 has previously been shown to be a possible osteoblastic differentiation inhibiting lncRNA. For this reason, Li et al [68] selected this lncRNA to confirm its role in osteoblast differentiation in vitro and in vivo. In vivo experiments carried out on two osteoporotic mouse models showed that its expression levels are significantly higher in the OVX mice and age-related osteoporotic groups compared, respectively, to sham-operated (Sham) and young groups, indicating that bone loss and bone structural deterioration are associated with elevated AK045490 expression levels.…”

Role of LncRNAs and CircRNAs in Bone Metabolism and Osteoporosis

“…Elevated lncRNA AK045490 is also reported to inhibit osteoblast differentiation of BMSCs, and its inhibition in vivo rescued bone formation in OVX osteoporosis mice. Furthermore, it is revealed that AK045490 targeted β-catenin and restricted its translocation into the nucleus, leading to suppression of Runx2, T-cell specific transcription factor (TCF1), and lymphoid enhancer binding factor (LEF1) expression and inhibition of osteoblast differentiation (Li et al, 2019a).…”