Regulatory mechanisms of autophagy-related ncRNAs in bone metabolic diseases

Abstract

Bone metabolic diseases have been tormented and are plaguing people worldwide due to the lack of effective and thorough medical interventions and the poor understanding of their pathogenesis. Non-coding RNAs (ncRNAs) are heterogeneous transcripts that cannot encode the proteins but can affect the expressions of other genes. Autophagy is a fundamental mechanism for keeping cell viability, recycling cellular contents through the lysosomal pathway, and maintaining the homeostasis of the intracellular environment. There is growing evidence that ncRNAs, autophagy, and crosstalk between ncRNAs and autophagy play complex roles in progression of metabolic bone disease. This review investigated the complex mechanisms by which ncRNAs, mainly micro RNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), regulate autophagic pathway to assist in treating bone metabolism disorders. It aimed at identifying the autophagy role in bone metabolism disorders and understanding the role, potential, and challenges of crosstalk between ncRNAs and autophagy for bone metabolism disorders treatment.

Keywords: autophagy; bone metabolism; ncRNAs; osteoarthritis; osteoporosis; rheumatoid arthritis.

FIGURE 1

The main stages of autophagy. Autophagy is an evolutionarily conserved dynamic way in the form of degradation, and it mainly consists of initiation, nucleation, prolongation, maturation, and degradation (Abbreviations: ATP, adenosine triphosphate; AMP, adenosine monophosphate; mTOR, mammalian target of rapamycin; AMPK, 5ʹ AMP-activated protein kinase; ULK1, UNC-51-like kinase; PI3K, phosphoinositide3 kinase; PI3P, phosphatidylinositol 3-phosphate; Akt, protein kinase B; ATG, autophagy-related protein; LC3, microtubule-associated protein 1 light chain 3; PE, phosphatidylethanolamine).

FIGURE 2

Cell types involved in bone metabolism and the roles of autophagy on OBs and OCs. Bone remodeling mainly refers to the OC-mediated bone resorption and OB-mediated bone formation. After the osteoblast differentiation, bone mineralization and bone reconstruction will be performed, marking the completion of bone remodeling. The dynamic balance between bone formation and degeneration is constantly harmonized (Abbreviations: RANK, receptor activator of NF-κB; RANKL, receptor activator of NF-κB ligand; TRAF6, tumor necrosis factor receptor-associated factor-6; Beclin-1, the autophagy markers; ATG, autophagy-related protein; LC3, microtubule-associated protein 1 light chain 3; CTSK, cathepsin K; MMM9, matrix metalloproteinase 9; mTOR, mammalian target of rapamycin; AMPK, 5ʹ AMP-activated protein kinase; Akt, protein kinase (B).

FIGURE 3

ncRNAs regulate autophagy and participate in the occurrence and development of bone metabolic diseases. (A) Biogenesis of ncRNAs (B) ncRNAs target autophagy related genes to regulate autophagy and then affect the occurrence and development of bone metabolic diseases (Abbreviations: Pol II, RNA polymerase II; pri-miRNA, primary miRNA; pre-miRNA, the precursor miRNA; RISC, RNA-induced silencing complex). Created with https://www.BioRender.com.