The role of autophagy in bone metabolism and clinical significance

Abstract

The skeletal system is the basis of the vertebral body composition, which affords stabilization sites for muscle attachment, protects vital organs, stores mineral ions, supplies places to the hematopoietic system, and participates in complex endocrine and immune system. Not surprisingly, bones are constantly reabsorbed, formed, and remodeled under physiological conditions. Once bone metabolic homeostasis is interrupted (including inflammation, tumors, fractures, and bone metabolic diseases), the body rapidly initiates bone regeneration to maintain bone tissue structure and quality. Macroautophagy/autophagy is an essential metabolic process in eukaryotic cells, which maintains metabolic energy homeostasis and plays a vital role in bone regeneration by controlling molecular degradation and organelle renewal. One relatively new observation is that mesenchymal cells, osteoblasts, osteoclasts, osteocytes, chondrocytes, and vascularization process exhibit autophagy, and the molecular mechanisms and targets involved are being explored and updated. The role of autophagy is also emerging in degenerative diseases (intervertebral disc degeneration [IVDD], osteoarthritis [OA], etc.) and bone metabolic diseases (osteoporosis [OP], osteitis deformans, osteosclerosis). The use of autophagy regulators to modulate autophagy has benefited bone regeneration, including MTOR (mechanistic target of rapamycin kinase) inhibitors, AMPK activators, and emerging phytochemicals. The application of biomaterials (especially nanomaterials) to trigger autophagy is also an attractive research direction, which can exert superior therapeutic properties from the material-loaded molecules/drugs or the material's properties such as shape, roughness, surface chemistry, etc. All of these have essential clinical significance with the discovery of autophagy associated signals, pathways, mechanisms, and treatments in bone diseases in the future.Abbreviations: Δψm: mitochondrial transmembrane potential AMPK: AMP-activated protein kinase ARO: autosomal recessive osteosclerosis ATF4: activating transcription factor 4 ATG: autophagy-related β-ECD: β-ecdysone BMSC: bone marrow mesenchymal stem cell ER: endoplasmic reticulum FOXO: forkhead box O GC: glucocorticoid HIF1A/HIF-1α: hypoxia inducible factor 1 subunit alpha HSC: hematopoietic stem cell HSP: heat shock protein IGF1: insulin like growth factor 1 IL1B/IL-1β: interleukin 1 beta IVDD: intervertebral disc degradation LPS: lipopolysaccharide MAPK: mitogen-activated protein kinase MSC: mesenchymal stem cell MTOR: mechanistic target of rapamycin kinase NP: nucleus pulposus NPWT: negative pressure wound therapy OA: osteoarthritis OP: osteoporosis PTH: parathyroid hormone ROS: reactive oxygen species SIRT1: sirtuin 1 SIRT3: sirtuin 3 SQSTM1/p62: sequestosome 1 TNFRSF11B/OPG: TNF receptor superfamily member 11b TNFRSF11A/RANK: tumor necrosis factor receptor superfamily, member 11a TNFSF11/RANKL: tumor necrosis factor (ligand) superfamily, member 11 TSC1: tuberous sclerosis complex 1 ULK1: unc-51 like autophagy activating kinase 1.

Keywords: Autophagy; bone metabolism; mesenchymal stem cell; osteoblast; osteoclast; osteogenesis.

Figure 1.

Schematic diagram of the three primary types of autophagy. (A) Macroautophagy/autophagy. (B) Chaperone-mediated autophagy. (C) Microautophagy. The main stages of macroautophagy are presented, including initiation, nucleation, expansion, closure and maturation, fusion, and degradation. All these processes help to complete the recycling of “waste” in the body.

Figure 2.

The role of autophagy in osteoblast and osteoclast involved in bone metabolism. Autophagy is activated under stress conditions (oxidative stress, hypoxia, starvation, inflammation); for osteoblast, ROS and ER stress participate in autophagy regulation, promote the reuse of intracellular substances and release vesicles to participate in the initial mineralization process; TNFRSF11B is a decoy receptor of TNFSF11 and competitively inhibits osteoclast differentiation and maturation by blocking the interaction between TNFSF11 and TNFRSF11A. TNFRSF11B inhibits osteoclast and bone resorption by enhancing autophagy through activation of AMPK-MTOR signaling pathway. For osteoclasts, autophagy is involved in forming the ruffled border and actin rings [33], as well as releasing lysosomal proteolytic enzymes, including CTSK and MMP9. Mitochondria can provide ATP and release acidic substances (such as citric acid and lactic acid) to the bone resorption pit. Mitophagy to clear the damaged mitochondria can counter osteoclast-derived bone resorption.

Figure 3.

Mitophagy and its role in osteoclastogenesis and osteoblast differentiation. ROS and other stresses (e.g., starvation and DNA damage) can destroy mitochondria and thereby lead to δψm depolarized in osteoclasts and osteoblasts to induce mitophagy in a PRKN-dependent manner: Mitochondria depolarize during stress conditions, phosphorylated PINK1 accumulates and subsequently recruit PRKN to mitochondria. PINK1 then induces phosphorylation of PRKN and ubiquitinated mitochondrial outer membrane proteins, which can bind LC3 directly in autophagosome membranes or indirectly through SQSTM1, OPTN, and CALCOCO2/NDP52. The process of mitophagy is completed through the ligand fusion of LC3-II and EGF5-RAB7-LRRK2 on lysosome. When osteoclasts and osteoblasts are deficient in energy, AMPK is activated and phosphorylates TSC2 to inhibit MTOR. Conversely, phosphorylation of AMPK at Ser317 and Ser777 activates ULK1, and the activated ULK1-ATG13-RB1CC1 protease complex stimulates autophagy and mitophagy.

Figure 4.

The role of autophagy in the association between different types of cells in OP pathogenesis. A) the early stage of OP is also known as the period of high bone turnover, which can last for 3–5 years. It is characterized as increased bone resorption and formation, but higher bone resorption efficiency leads to net bone loss. B) GC-induced OP with increased bone resorption but decreased bone formation. Autophagy is mainly involved in bone resorption and osteocyte survival. C) Senile OP, characterized by persistent slow bone loss, entails the resorption cavity and porosity increasing progressively, and the osteocytes autophagy is gradually inhibited with aging. D) Inflammation-related OP, enhanced autophagy participates in osteoclast-mediated bone resorption, which is the primary mechanism leading to bone loss.