CXCL12 chemokine up‐regulates bone resorption and MMP‐9 release by human osteoclasts: CXCL12 levels are increased in synovial and bone tissue of rheumatoid arthritis patients

Abstract

Chemokines are involved in a number of inflammatory pathologies and some of them show a pivotal role in the modulation of osteoclast development. Therefore, we evaluated the role of CXCL12 chemokine on osteoclast differentiation and function and we analyzed its expression on synovial and bone tissue biopsies from rheumatoid arthritis (RA) patients. Osteoclasts were obtained by 7 days in vitro differentiation with RANKL and M-CSF of CD11b positive cells in the presence or absence of CXCL12. The total number of osteoclast was analyzed by Tartrate-resistant acid phosphatase (TRAP)-staining and bone-resorbing activity was assessed by pit assay. MMP-9 and TIMP-1 release was evaluated by ELISA assay. CXCL12 expression on biopsies from RA patients was analyzed by immunohistochemistry. Osteoclasts obtained in the presence of CXCL12 at 10 nM concentration displayed a highly significant increase in bone-resorbing activity as measured by pit resorption assay, while the total number of mature osteoclasts was not affected. The increased resorption is associated with overexpression of MMP-9. Immunostaining for CXCL12 on synovial and bone tissue biopsies from both rheumatoid arthritis (RA) and osteoarthritis (OA) samples revealed a strong increase in the expression levels under inflammatory conditions. CXCL12 chemokine showed a clear activating role on mature osteoclast by inducing bone-resorbing activity and specific MMP-9 enzymatic release. Moreover, since bone and synovial biopsies from RA patients showed an elevated CXCL12 expression, these findings may provide useful tools for achieving a full elucidation of the complex network that regulates osteoclast function in course of inflammatory diseases.

DNA methylation regulates the expression of CXCL12 in rheumatoid arthritis synovial fibroblasts

“…55,56 The chemokine CXCL12 was reported to induce the expression of MMP-3 in chondrocytes and of MMP-9 in osteoclasts. 16,22 Furthermore, increased gelatinase and collagenase activity was described after CXCL12 stimulation in SFs. 23 Our present data suggest that the increased collagenase activity after CXCL12 stimulation stems from increased transcription of MMP-1 and MMP-13.…”

“…16,22,23 As DNA demethylation induces CXCL12 overexpression, we measured mRNA expression of the collagenases MMP-1 and MMP-13, the gelatinases MMP-2 and MMP-9, stromelysin (MMP-3), and the matrix-bound MMP-14 after stimulation with CXCL12 for 24 h in RASFs. In addition, we looked at the mRNA expression of the tissue inhibitors of MMPs (TIMPs) À1, À2 and À3.…”

Tumor Angiogenesis Is Associated with Plasma Levels of Stromal-Derived Factor-1α in Patients with Multiple Myeloma

“…These actions include the mobilization and adhesion of multiple myeloma plasma cells to stroma (11), the proliferation and migration of multiple myeloma plasma cells (12), the recruitment of osteoclasts to the bone marrow (13), and, most recently, the enhancement of osteoclastic bone resorption (14, 15). In this study, we determined whether multiple myeloma plasma cell -derived SDF-1a could stimulate angiogenesis in vitro and examined whether SDF-1a promotes angiogenesis in multiple myeloma patients.…”

Upregulation of stromal cell derived factor-1α in collagen vascular diseases-associated interstitial pneumonias (CVDs-IPs)

“…been found that the concentration of CXCL12 is elevated in plasma and synovial fluid specimens from patients with RA (33,34), and an overexpression of CXCL12 is also observed in RA synovial tissue (35)(36). CXCL12 promotes CD4+ memory T-cells recruitment and accumulation (37) and monocyte migration into synovium (38) …”