The molecular structure and role of CCL2 (MCP‐1) and C‐C chemokine receptor CCR2 in skeletal biology and diseases

Abstract Monocyte chemoattractant protein‐1, also called chemokine (C‐C motif) ligand 2 (CCL2) or small inducible cytokine A2, is an inflammatory mediator capable of recruiting monocytes, memory T cells, and dendritic cells. CCL2 is a member of the CC chemokine superfamily, which binds to its receptor, C‐C motif chemokine receptor‐2 (CCR2), for the induction of chemotactic activity and an increase of calcium influx. It exerts multiple effects on a variety of cells, including monocytes, macrophages, osteoclasts, basophils, and endothelial cells, and is involved in a diverse range of diseases. This review discusses the molecular structure and role of CCL2 and CCR2 in skeletal biology and disease. Molecular structure analyses reveal that CCL2 shares a conserved C‐C motif; however, it has only limited sequence homology with other CCL family members. Likewise, CCR2, as a member of the G‐protein‐coupled seven‐transmembrane receptor superfamily, shares conserved cysteine residues, but exhibits very limited sequence homology with other CCR family members. In the skeletal system, the expression of CCL2 is regulated by a variety of factors, such as parathyroid hormone/parathyroid hormone‐related peptide, interleukin 1b, tumor necrosis factor‐α and transforming growth factor‐beta, RANKL, and mechanical forces. The interaction of CCL2 and CCR2 activates several signaling cascades, including PI3K/Akt/ERK/NF‐κB, PI3K/MAPKs, and JAK/STAT‐1/STAT‐3. Understanding the role of CCL2 and CCR2 will facilitate the development of novel therapies for skeletal disorders, including rheumatoid arthritis, osteolysis and other inflammatory diseases related to abnormal chemotaxis.