Roles of Altered Macrophages and Cytokines: Implications for Pathological Mechanisms of Postmenopausal Osteoporosis, Rheumatoid Arthritis, and Alzheimer's Disease

Abstract

Postmenopausal osteoporosis (PMOP) is characterized by the uncoupling of bone resorption and bone formation induced by estrogen deficiency, which is a complex outcome related to estrogen and the immune system. The interaction between bone and immune cells is regarded as the context of PMOP. Macrophages act differently on bone cells, depending on their polarization profile and secreted paracrine factors, which may have implications for the development of PMOP. PMOP, rheumatoid arthritis (RA), and Alzheimer's disease (AD) might have pathophysiological links, and the similarity of their pathological mechanisms is partially visible in altered macrophages and cytokines in the immune system. This review focuses on exploring the pathological mechanisms of PMOP, RA, and AD through the roles of altered macrophages and cytokines secretion. First, the multiple effects on cytokines secretion by bone-bone marrow (BM) macrophages in the pathological mechanism of PMOP are reviewed. Then, based on the thought of "different tissue-same cell type-common pathological molecules-disease pathological links-drug targets" and the methodologies of "molecular network" in bioinformatics, highlight that multiple cytokines overlap in the pathological molecules associated with PMOP vs. RA and PMOP vs. AD, and propose that these overlaps may lead to a pathological synergy in PMOP, RA, and AD. It provides a novel strategy for understanding the pathogenesis of PMOP and potential drug targets for the treatment of PMOP.

Keywords: Alzheimer’s disease; cytokines; macrophages; postmenopausal osteoporosis; rheumatoid arthritis.

Graphical Abstract

Figure 1

Top 20 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment candidate targets of differential genes in postmenopausal osteoporosis. Pathways with significant changes (false discovery rate [FDR] < 0.05) were identified. The vertical coordinates represent the KEGG pathway with significant enrichment, and the horizontal coordinates represent the gene ratio, which refers to the ratio of enriched genes to all target genes. The color of the bubble graph indicates the significance of the enriched KEGG pathway, the color gradient represents the size of the P-value, and the size of each dot represents the number of genes.

Figure 2

Core cytokine networks of pathological crosstalk in postmenopausal osteoporosis (PMOP) vs. rheumatoid arthritis (RA) and PMOP vs. Alzheimer’s disease (AD). Gene ontology functional enrichment analysis of common differential genes in PMOP vs. RA and PMOP vs. AD was performed, including biological processes (A, D) and molecular functions (B, E). Protein–protein interaction (PPI) network topology analysis was performed for common differential genes in PMOP vs. RA and PMOP vs. AD, and biological process enrichment analysis of core network genes was completed (C, F).