Chemokines in Physiological and Pathological Bone Remodeling

Abstract

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.

Keywords: bone remodeling; chemokines; osteoblasts; osteoclasts; osteoimmunology.

Figure 1

Summary of chemokine influences on bone formation and/or resorption. Osteoblasts and osteoclasts are distinctive cell types required for bone formation and bone resorption, respectively. Whereas osteoblasts (left) derive from mesenchymal stem cells, osteoclasts (right) are generated by fusion of hematopoietic progenitor cells. This simplified schematic representation summarizes chemokines and chemokine receptors for which an influence on either bone formation and/or bone resorption was established. Positive influences are indicated in green (with the “+” symbol) whereas negative influences are indicated in red (with the “–” symbol). The data supporting these influences, the underlying mechanisms and the impact on pathological conditions are discussed in the text.

Figure 2

Bone remodeling phenotype of Ccl5-deficient mice. (A) Representative images of undecalcified spine sections (von Kossa/van Gieson-staining, mineralized bone appears black) from 6-month-old littermate mice with the indicated genotypes showing reduced trabecular bone mass in Ccl5-deficient animals. (B) Representative images of tibia sections stained for activity of the osteoclast marker TRAP (tartrate-resistant acid phosphatase, red staining) from the same mice demonstrating increased osteoclastogenesis in Ccl5-deficient animals. (C) Histomorphometric quantification of the osteoclast number per bone perimeter (Oc.N/B.Pm) in wildtype and Ccl5-deficient littermate mice at the ages of 3, 6, and 12 months. Asterisks indicate significant differences (*p < 0.05). (D) Representative images of undecalcified tibia sections (toluidine blue staining) from 6-month-old littermate mice with the indicated genotypes show that the majority of endocortical bone surfaces in Ccl5-deficient animals are not covered by osteoblasts. (E) Quantification of the endocortical osteoblastic cell-free bone surface (BS) in wildtype and Ccl5-deficient littermate mice does not only demonstrate the severity of this phenotype at 3 and 6 months of age, but also that this pathology is normalized in 12-month-old animals. Asterisks indicate significant differences (*p < 0.05). These data are based on a published study (57).

Figure 3

The CXCL12/CXCR4 axis in physiological and pathological bone remodeling. Numerous studies have established that the CXCL12/CXCR4 axis is not only required for homing of hematopoietic stem cells, but also for the regulation of bone remodeling cell types in physiological and pathological conditions. (1) CXCL12, which is predominantly expressed by CXCL12-abundant reticular (CAR) cells, binds to CXCR4 on hematopoietic stem cells to recruit them to bone microenvironment. (2) This mechanism is also used by CXCR4-expressing metastatic cancer cells which explains their recruitment to the bone marrow niche. (3) CXCL12 expression by multiple myeloma cells enhances recruitment and maturation of pre-osteoclasts by inducing RANK expression. (4) Osteoblasts also express CXCL12 to physiologically regulate migration and maturation of osteoclast progenitor cells. (5) CXCL12 additionally cooperates with BMP signaling to promote osteogenic differentiation of mesenchymal stromal cells.