Chemokines in Physiological and Pathological Bone Remodeling

The bone matrix is constantly remodeled by bone-resorbing osteoclasts and bone-forming osteoblasts. These two cell types are fundamentally different in terms of progenitor cells, mode of action and regulation by specific molecules, acting either systemically or locally. Importantly, there is increasing evidence for an impact of cell types or molecules of the adaptive and innate immune system on bone remodeling. Understanding these influences is the major goal of a novel research area termed osteoimmunology, which is of key relevance in the context of inflammation-induced bone loss, skeletal metastases, and diseases of impaired bone remodeling, such as osteoporosis. This review article aims at summarizing the current knowledge on one particular aspect of osteoimmunology, namely the impact of chemokines on skeletal cells in order to regulate bone remodeling under physiological and pathological conditions. Chemokines have key roles in the adaptive immune system by controlling migration, localization, and function of immune cells during inflammation. The vast majority of chemokines are divided into two subgroups based on the pattern of cysteine residues. More specifically, there are 27 known C-C-chemokines, binding to 10 different C-C receptors, and 17 known C-X-C-chemokines binding to seven different C-X-C receptors. Three additional chemokines do not fall into this category, and only one of them, i.e., CX3CL1, has been shown to influence bone remodeling cell types. There is a large amount of published studies demonstrating specific effects of certain chemokines on differentiation and function of osteoclasts and/or osteoblasts. Chemokine signaling by skeletal cells or by other cells of the bone marrow niche regulates bone formation and resorption through autocrine and paracrine mechanisms. In vivo evidence from mouse deficiency models strongly supports the role of certain chemokine signaling pathways in bone remodeling. We will summarize these data in the present review with a special focus on the most established subsets of chemokines. In combination with the other review articles of this issue, the knowledge presented here confirms that there is a physiologically relevant crosstalk between the innate immune system and bone remodeling cell types, whose molecular understanding is of high clinical relevance.