Communications Between Bone Marrow Macrophages and Bone Cells in Bone Remodeling

Abstract

The mammalian skeleton is a metabolically active organ that continuously undergoes bone remodeling, a process of tightly coupled bone resorption and formation throughout life. Recent studies have expanded our knowledge about the interactions between cells within bone marrow in bone remodeling. Macrophages resident in bone (BMMs) can regulate bone metabolism via secreting numbers of cytokines and exosomes. This review summarizes the current understanding of factors, exosomes, and hormones that involved in the communications between BMMs and other bone cells including mensenchymal stem cells, osteoblasts, osteocytes, and so on. We also discuss the role of BMMs and potential therapeutic approaches targeting BMMs in bone remodeling related diseases such as osteoporosis, osteoarthritis, rheumatoid arthritis, and osteosarcoma.

Keywords: bone diseases; bone remodeling; intracellular communication; macrophage-derived exosome; macrophages.

Figure 1

Origin and classification of macrophages. The diagram illustrates the source and classification of macrophages. Circulating macrophages are classified into M1 and M2 types according to their activators and functions. M2-type can be further subdivided into M2a, M2c, and M2d by different signal activation, cell surface markers and their functions. Based on the origin, tissue-resident macrophages can be divided into two subsets. One derives from the yolk sac and another population originates from hematopoietic progenitors and circulating monocytes. Bone macrophage includes bone marrow macrophage (erythroblastic island macrophage, hematopoietic stem cell niche macrophage), osteoclast and osteal macrophages (osteomacs).

Figure 2

Communications between macrophages and bone remodeling cells. Arrow represents “stimulatory modification;” the gray triangle means “enlarged display;” the arrow with a line means “suppress.” Cell-cell communication between MSCs and macrophages results in the production of PGE2 and through the EP2/4 receptors to produce OSM. OSM acts on the MSCs via the gp130 receptors to activate STAT3 phosphorylation. Macrophage can also release BMP-2 to active the osteoblast differentiation genes, such as ALP, via the BMP-R in MSCs. MSCs can produce CCL-2 and CCL-4 to regulate macrophages and in reverse, this process is under the control of the macrophages; The differentiation of osteoblasts is regulated by variety of aspects including macrophages, osteocytes, inflammatory mediators and MSCs; Osteoclasts and osteomacs can derive from the same myeloid precursor, but it's unknown if the osteomac is a kind of the osteoclast precursors. Besides, macrophages mediate the growth of osteoclasts through various cytokines; Osteocytes apoptosis is under the regulation of macrophages.

Figure 3

Macrophage-derived exosomes in bone metabolism. Arrow represents “stimulatory modification;” the gray triangle means “enlarged display.” The structure of macrophage derived exosomes is phospholipid bilayer with a diameter between 30 and 150 nm. Macrophage derived exosomes contain miRNAs (such as mir-21, mir-155, and mir-5106) and alarmins (such as Annexin, Galectin, HSP, and Fibronectin), all of them can through diverses signal pathways or release relative cytokines to participate in variety organs metabolism, including bone remodeling.

Figure 4

Macrophage and regulatory hormones and factors. Arrow represents “stimulatory modification;” the gray triangle means “enlarged display.” Macrophages play a part in the anabolic response to intermittent PTH therapy via osteoblasts which can secrete factors (IL-6, etc.) that promote the differentiation and recruitment of macrophages; Worthy to be mentioned the work of CSF-1 and Ca²⁺ on macrophages; Macrophage-derived BMP-2 has effect on BMSCs, osteoblasts and macrophages via BMP-R to accelerate the osteogenic differentiation so as to make bone metabolism balance; Estrogen regulates bone homeostasis mainly through osteoblasts and osteoclasts. Estrogen mainly affects the activity of macrophages by interfering with the macrophage-mediated osteoclast formation process.

Figure 5

Macrophage and bone remodeling related diseases. Arrow represents “stimulatory modification;” the gray triangle means “enlarged display.” Osteoporosis is an age-related bone disease to some extent. The release and accumulation of proinflammatory cytokines can active osteoclasts and thus greatly accelerate the process of osteoporosis; The patients of osteoarthritis have a vital inducer that is tissue damage which can release various cytokines, leading to the imbalance between M1 and M2 macrophages. Usually, the quantity of M1 prevails, leading to the aggravation of OA; Caspase-8/RIPK3 signaling pathway and HIF1-α have been found to play a role in regulating macrophages, through CD206 and glycolysis, respectively. Besides, macrophages can secret IL-26, an inducer of Th17 cells which can cause autoimmune tissue damage; Osteosarcoma always occurs in the metaphyseal region of the long bone and the growth and metastasis of tumor cells have a closely relationship with IL-34 and CCL18. Moreover, tumor cell-derived IL-34 stimulates the angiogenesis of TAM. Cancer-related thrombosis could be made by the interaction of clec-2-podoplanin and the ectopic expression of podoplanin in patient's macrophages is the inducer, leading to the severe complications.