HOXC10 Regulates Osteogenesis of Mesenchymal Stromal Cells Through Interaction with Its Natural Antisense Transcript lncHOXC-AS3

Abstract

The characteristics of mesenchymal stromal cells (MSCs) which derived from multiple myeloma (MM) patients are typically impaired in osteogenic differentiation. However, the underlying molecular mechanisms need to be further investigated. lncRNAs are emerging as critical regulation molecules in oncogenic pathways. In this study, we identified that bioactive lncRNA HOXC‐AS3, which is transcribed in opposite to HOXC10, was presented in MSCs derived from bone marrow (BM) of MM patients (MM‐MSCs). HOXC‐AS3 was able to interact with HOXC10 at the overlapping parts and this interaction increased HOXC10 stability, then promoted its expression, conferring osteogenesis repression to MM‐MSCs. In mouse models, intravenously administered siHOXC‐AS3 was proven to be effective in prevention of bone loss, sustained by both anticatabolic activities and bone‐forming. These data showed that lncHOXC‐AS3 was required for osteogenesis in BM‐MSCs by enhancing HOXC10 expression. Our finding thus unveils a novel insight for the potential clinical significance of lncRNA HOXC‐AS3 as a therapeutic target for bone disease in MM. Stem Cells 2019;37:247–256

DNA methylation across the genome in aged human skeletal muscle tissue and muscle-derived cells: the role of HOX genes and physical activity

“…HOXC-AS3 is a long coding RNA (lcRNA) with currently no known data in skeletal muscle, with some literature in cancer and mesenchymal stem cell (MSC) fields 76 . Indeed, MSC’s administered with silencing HOXC-AS3 prevented bone loss by enhancing HOXC10 expression 77 , and HOXC-AS3 upregulation has also been linked with aggressive cancer 78 . Interestingly, we were able to identify that together with associated hypomethylation, in a region close to the lcRNA HOXC-AS3, there was significantly increased gene expression of HOXC-AS3 (and an average, yet not significant increase in HOXC10 gene expression) in aged muscle cells at 7 days of differentiation.…”

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

“…By establishing depleted and transgenic overexpression of lnc-Bmncr mice, Li et al evaluated the function of Bmncr in BMSCs on age-related switch between osteoblast and adipocyte differentiation [28]. It was proved that intravenously administered siHOXC-AS3 was effective in prevention of bone loss, sustained by both anticatabolic activities and bone-forming in mouse models [29]. Silencing lncRNA MEG3 in tibia fracture mice models by siRNA could accelerate tibia fraction healing via activating the Wnt/beta-catenin signaling pathway [30].…”

Non-Coding RNAs in Multiple Myeloma Bone Disease Pathophysiology

“…HOXC-AS3 interacts with HOXC10 at the overlapping parts thus strengthening its stability and promoting its expression; consequently, up-regulation of HOXC10 contributed to repressing osteogenic potential of MSCs [ 110 ]. The effect of HOXC-AS3 on osteogenic differentiation was evaluated in vivo, by using a “human-in-mouse” xeno-transplantation MM model, which included the MM clinical signs such as BD.…”

“…To analyze bone loss in the mouse models, trabecular and cortical bone were evaluated by micro CT images; results obtained indicated severe bone loss in the vehicle control group, compared to the HOXC-AS3 siRNA-treated mice group. In addition, HOXC-AS3 siRNA significantly altered bone turnover markers levels in serum; in particular, the bone resorption marker C-terminal telopeptide of type 1 collagen (CTX) was reduced in HOXC-AS3 siRNA group, while the bone formation marker, procollagen type 1 N-terminal propeptide (P1NP), increased [ 110 ].…”