The Autophagy in Osteoimmonology: Self-Eating, Maintenance, and Beyond

Abstract

It has been long realized that the immune and skeletal systems are closely linked. This crosstalk, also known as osteoimmunology, is a primary process required for bone health. For example, the immune system acts as a key regulator in osteoclasts-osteoblasts coupling to maintain the balanced bone remodeling. Osteoimmunology is achieved through many cellular and molecular processes, among which autophagy has recently been found to play an indispensable role. Autophagy is a highly conserved process in eukaryotic cells, by which the cytoplasm components such as dysfunctional organelles are degraded through lysosomes and then returned to the cytosol for reuse. Autophagy is present in all cells at basal levels to maintain homeostasis and to promote cell survival in response to cellular stress conditions such as nutrition deprivation and hypoxia. Autophagy is a required process in immune cell activation/polarization and osteoclast differentiation, which protecting cells from oxidative stress. The essential of autophagy in osteogenesis is its involvement in osteoblast differentiation and mineralization, especially the role of autophagosome in extracellular calcium transportation. The modulatory feature of autophagy in both immune and skeleton systems suggests its crucial roles in osteoimmunology. Furthermore, autophagy also participates in the maintenance of bone marrow hematopoietic stem cell niche. The focus of this review is to highlight the role of autophagy in the immune-skeleton interactions and the effects on bone physiology, as well as the future application in translational research.

Keywords: autophagy; bone remodeling; immunomodulation; osteoimmunology; stem cell.

Figure 1

The role of autophagy in the differentiation/function of osteoclast, osteoblast and osteocyte. During RANKL-RANK induced osteoclast differentiation, the protein levels of ATG5/7/12 are increased, accompanied with enhanced conversion from LC3-I to LC3-II and p62 degradation, which plays an essential role in the generation of F-actin ring. Besides differentiation, autophagy also plays decisive roles in osteoclast function, that the physiological levels of Atg5/7/4B are required for lysosomal [containing H⁺ and cathepsin K (CatK)] trafficking and fusion with the plasma membrane to generate mature ruffled border, as well as to release H⁺ and cathepsin K to resorb bone. During osteoblast differentiation, the binding of BMP2 to its receptors (BMPR) activates Smad signaling pathway to initiate osteogenesis, which also induced the expression of beclin 1 and LAMP2 (autophagy-related proteins) as well as autophagy pathway. Autophagosomes are utilized for transporting mineral crystals to extracellular matrix and thereby facilitating mineralization. Autophagy reduces oxidative stress during osteoblast differentiation via clearance of damaged mitochondria, which also suppresses RANKL production and hence inhibiting osteoclastogenesis. Compared with osteoblast, the autophagy level is increased in osteocyte, which not only maintains homeostasis of osteocyte, but also guarantees a physiological osteocyte-derived regulation on bone remodeling.

Figure 2

A proposed effect in osteoimmunology regarding biomaterial with the property of inducing autophagy (autophagy-biomaterial). The autophagy-biomaterial should induce bone repair by suppressing the inflammatory response. On one hand, autophagy-induction directly reduces macrophage inflammation and IL-1β secretion. The decreased IL-1β also impedes the polarization and function of Th17 cell (Th17). On the other hand, autophagy-induction in dendritic cell (DC) interrupts its interaction with T cells, thereby inhibiting T cell inflammatory response via introducing the polarization from Th1 toward Th2 cells, as well as that from Th17 to Treg cells. The Th1 to Th2 conversion would in turn reduce M1 polarization while induce M2 polarization. Hence, the autophagy-biomaterial creates an immune microenvironment favoring bone regeneration: the limited inflammatory responses of T cell and M1 macrophage reduce osteoclastogenesis, while the conversion of M1 to M2 macrophages improves osteogenesis.