Stromal Cell-Derived Factor-1 (SDF-1) Recruits Osteoclast Precursors by Inducing Chemotaxis, Matrix Metalloproteinase-9 (MMP-9) Activity, and Collagen Transmigration

Abstract

Signals targeting OCs to bone and resorption sites are not well characterized. A chemoattractant receptor (CXCR4), highly expressed in murine OC precursors, mediated their chemokine (SDF-1)-induced chemoattraction, collagen transmigration, and MMP-9 expression. Thus, bone vascular and stromal SDF-1 may direct OC precursors into bone and marrow sites for development and bone resorption.Introduction: Although chemokines are essential for trafficking and homing of circulating hematopoietic cells under normal and pathological conditions, their potential roles in osteoclast (OC) recruitment or function are generally unknown. CXCR4 and its unique ligand, stromal cell-derived factor-1 (SDF-1), critically control the matrix metalloproteinase (MMP)-dependent targeting of hematopoietic cells into bone and within the marrow microenvironment. Therefore, SDF-1/CXCR4 may regulate OC precursor recruitment to sites for development and activation. Methods: Chemokine receptor mRNA expression was analyzed during OC formation induced by RANKL in murine RAW 264.7 cells. SDF-1 versus RANKL effects on chemotaxis, transcollagen migration, MMP-9 expression and activity, OC development, and bone resorption were evaluated in RAW cells or RAW-OCs. Results: CXCR4 was highly expressed in RAW cells and downregulated during their RANKL development into bone-resorptive RAW-OCs. SDF-1, but not RANKL, elicited RAW cell chemotaxis. Conversely, RANKL, but not SDF-1, promoted RAW-OC development, TRAP activity, cathepsin K expression, and bone pit resorption, and SDF-1 did not modify these RANKL responses. Both SDF-1 and RANKL increased MMP-9, a matrix-degrading enzyme essential for OC precursor migration into developing bone marrow cavities, and increased transcollagen migration of RAW cells in a MMP-dependent manner. SDF-1 also upregulated MMP-9 in various primary murine OC precursor cells. Because RANKL induced a higher, more sustained expression of MMP-9 in RAW cells than did SDF-1, MMP-9 may have an additional role in mature OCs. Consistent with this, MMP-9 upregulation during RANKL-induced RAW-OC development was necessary for initiation of bone pit resorption. Conclusions: SDF-1, a chemokine highly expressed by bone vascular endothelial and marrow stromal cells, may be a key signal for the selective attraction of circulating OC precursors into bone and their migration within marrow to appropriate perivascular stromal sites for RANKL differentiation into resorptive OCs. Thus, SDF-1 and RANKL likely serve complementary physiological functions, partly mediated through increases in MMP-9, to coordinate stages of OC precursor recruitment, development, and function.

Recruitment of osteoclast precursors by stromal cell derived factor‐1 (SDF‐1) in giant cell tumor of bone

“…Gonzola et al showed that the SDF-l/CXCR4 axis is critical in mediating lung inflammation [ 151. Following attraction of precursors by the SDF-1/CXCR4 interaction, subsequent induction of matrix metalloproteinase-9 by SDF-1 was suggested to facilitate transmigration through the endothelial cell layer of blood vessels and homing in bones [30].…”

The pathogenesis of the bone disease of multiple myeloma

“…Its receptor is CXCR4 which expressed on hematopoeitic stem cells and lymphocytes, as well as malignant cells and osteoclast precursors (41)(42)(43). SDF-1 is expressed by bone marrow stromal cells and endothelial cells.…”

Osteoprotegerin exposure at different stages of osteoclastogenesis differentially affects osteoclast formation and function

“…If this enzyme function is compromised, mineral dissolution does not occur (Kornak et al 2000). Matrix metallopeptidase-9 (MMP-9) appears to be essential for osteoclast migration and precursor recruitment into bone (Okada et al 1995;Yu et al 2003). Although MMP-9-knockout mice show defects in bone development, intraosseous angiogenesis and fracture repair rather than osteoclast bone resorption appear to be compromised in these animals (Colnot et al 2003).…”