CK?-8 [CCL23], a novel CC chemokine, is chemotactic for human osteoclast precursors and is expressed in bone tissues

Abstract

We have previously demonstrated that a tartrate-resistant acid phosphatase (TRAP)-positive subpopulation of mononuclear cells isolated from collagenase digests of human osteoclastoma tissue exhibits an osteoclast phenotype and can be induced to resorb bone. Using these osteoclast precursors as a model system, we have assessed the chemotactic potential of 16 chemokines. Three CC chemokines, the recently described CKbeta-8, RANTES, and MIP-1alpha elicited significant chemotactic responses. In contrast, 10 other CC chemokines (MIP-1beta, MCP-1, MCP-2, MCP-3, MCP-4, HCC-1, eotaxin-2, PARC, SLC, ELC) and 3 CXC chemokines (IL-8, GROalpha, SDF-1) were inactive. None of these chemokines showed any chemotactic activity for either primary osteoblasts derived from human bone explants or the osteoblastic MG-63 cell line. The identity of the osteoclast receptor that mediates the chemotactic response remains to be established. However, all three active chemokines have been reported to bind to CCR1 and cross-desensitization studies demonstrate that RANTES and MIP-1alpha can partially inhibit the chemotactic response elicited by CKbeta-8. CKbeta-8, the most potent of the active CC chemokines (EC(max) 0.1-0.3 nM), was further characterized with regard to expression in human bone and cartilage. Although expression is not restricted to these tissues, CKbeta-8 mRNA was shown to be highly expressed in osteoblasts and chondrocytes in human fetal bone by in situ hybridization. In addition, CKbeta-8 protein was shown to be present in human osteophytic tissue by immunolocalization. These observations suggest that CKbeta-8, and perhaps other chemokines, may play a role in the recruitment of osteoclast precursors to sites of bone resorption.

Dual effects of macrophage inflammatory protein-1α on osteolysis and tumor burden in the murine 5TGM1 model of myeloma bone disease

“…MIP-1␣ is produced excessively by freshly isolated malignant plasma cells from patients and human myeloma cell lines [11][12][13] and is present in the bone marrow and marrow supernatants of myeloma patients with bone disease at much higher levels compared with patients with no bone disease and those with other hematologic malignancies and normal controls. [11][12][13][14] It was surmised that the chemokine may play a role as a mediator in the bone disease associated with myeloma, [11][12][13] because MIP-1␣ stimulates not only chemotaxis of monocyte-macrophage lineage cells (including osteoclast precursors and mature osteoclasts) 15 Here we show that functional blockade of MIP-1␣ bioactivity with neutralizing anti-MIP-1␣ antibodies attenuates tumor-induced lytic bone lesions in murine 5TGM1 myeloma-bearing mice, consistent with the notion that the chemokine plays an important role in the osteolysis associated with myeloma in vivo. Surprisingly, we also found a concomitant decrease in overall tumor burden, suggesting a previously unrecognized effect of MIP-1␣ on myeloma tumor progression.…”

“…14 MIP-1␣ stimulates chemotaxis of human osteoclast precursors 15 and formation of human osteoclast-like cells in vitro. 12,15,16 In nonhuman systems, The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 U.S.C.…”

“…11,12 Gene expression profiling studies also show that MIP-1␣ expression in mononuclear cells isolated from the bone marrow of myeloma patients is several-fold higher than in those from healthy subjects. 14 MIP-1␣ stimulates chemotaxis of human osteoclast precursors 15 and formation of human osteoclast-like cells in vitro. 12,15,16 In nonhuman systems, MIP-1␣ has also been shown to be chemotactic for cells at various stages in osteoclast ontogeny including murine granulocytemacrophage colony-forming units (CFU-GMs) 17 as well as isolated rat osteoclasts.…”

“…14 MIP-1␣ stimulates chemotaxis of human osteoclast precursors 15 and formation of human osteoclast-like cells in vitro. 12,15,16 In nonhuman systems, MIP-1␣ has also been shown to be chemotactic for cells at various stages in osteoclast ontogeny including murine granulocytemacrophage colony-forming units (CFU-GMs) 17 as well as isolated rat osteoclasts. 18 MIP-1␣ also stimulates the formation of osteoclastlike cells in rat, rabbit, and porcine bone cell cultures.…”

The Major Outer Membrane Protein of a Periodontopathogen Induces IFN-β and IFN-Stimulated Genes in Monocytes via Lipid Raft and TANK-Binding Kinase 1/IFN Regulatory Factor-3

“…RANTES is a CC chemokine and is involved in the activation and recruitment of neutrophils, eosinophils, monocytes, and Th1 cells to sites of infection. It is also a chemotactic factor for osteoclasts associated with bone resorption (43). RANTES was detected at significantly higher levels in gingival crevicular fluid from chronic periodontitis and generalized aggressive periodontitis, and it was positively correlated with both probing depth and clinical attachment loss (44,45).…”