CCL20 chemokine induces both osteoblast proliferation and osteoclast differentiation: Increased levels of CCL20 are expressed in subchondral bone tissue of rheumatoid arthritis patients

Abstract

We evaluated the role of CCL20 (MIP-3alpha) chemokine in cells directly involved in the remodeling of bone tissue (osteoblasts and osteoclasts) and we confirmed its expression in the subchondral bone tissue of rheumatoid arthritis (RA) patients. The expression of CCL20 and of its receptor CCR6 was evaluated in osteoblasts isolated from bone tissue of post-traumatic (PT) patients. Functional tests were performed to evaluate osteoblast proliferation and matrix protein modulation. Immunohistochemical analysis for CCR6, CCL20, and RANKL was performed on bone samples from RA patients. The role of CCL20 was then analyzed in osteoclast differentiation. We found that in basal conditions CCR6, but not its ligand CCL20, was highly expressed by osteoblasts. Functional analysis on osteoblasts showed that CCL20 significantly increased cellular proliferation but did not affect matrix protein expression. Pro-inflammatory cytokines significantly induced the release of CCL20 and RANKL by human osteoblasts but did not modulate CCR6 expression. Increased expression of CCR6, CCL20, and RANKL was confirmed in RA subchondral bone tissue biopsies. We demonstrated that CCL20 was also an earlier inducer of osteoclast differentiation by increasing the number of pre-osteoclasts, thus favoring cell fusion and MMP-9 release. Our results add new insight to the important role of the CCL20/CCR6, RANKL system in the bone tissue of RA. The contemporary action of CCL20 on osteoblasts and osteoclasts involved in the maintenance of bone tissue homeostasis demonstrates the important role of this compartment in the evolution of RA, by showing a clear uncoupling between new bone formation and bone resorption.

CC-Chemokine Ligand 20/Macrophage Inflammatory Protein-3α and CC-Chemokine Receptor 6 Are Overexpressed in Myeloma Microenvironment Related to Osteolytic Bone Lesions

“…Human osteoblasts (hOB) were isolated from the iliac crest biopsies obtained from healthy or MGUS patients after collagenase digestion according to the method used by Robey and Termine, as previously published (20,23). hOBs were fixed in 4% paraformaldehyde and analyzed using a FACStar Plus cytometer (Becton Dickinson) for the expression of osteoblast markers.…”

“…CC-chemokine ligand 20 (CCL20)/MIP-3a and its selective receptor CC-chemokine receptor 6 (CCR6), known to be responsible for the chemoattraction of dendritic, T, and B cells in homeostatic conditions (17), have been recently involved in rheumatoid arthritis synovitis (17)(18)(19) and OC activation in rheumatoid arthritis patients being overexpressed in subchondral bone tissues (20). Moreover, it has been shown that the overexpression of CCR6 by Langerhans cells in malignant histiocytosis contributes to their accumulation in the bone together with CCL20/MIP-3a overproduction by osteoblasts in the involved bone (21).…”

Induction of osteoclast progenitors in inflammatory conditions: key to bone destruction in arthritis

“…It also attracts OCPs to bone surfaces, and activates T lymphocytes and synovial fibroblasts in RA to secrete RANKL [43,60,78]. CCL20 is over-expressed in subchondral bone in RA, and is able to induce OCP expansion and osteoclast differentiation [79] Although treatment of RA patients with anti-CCL2 antibody failed to produce clinical improvement, recent studies revealed that serum CCL2 level is associated with osteoclastogenic potential of peripheral blood OCPs and clinical markers of arthritis activity [52,80].…”

Adipocyte culture medium stimulates invasiveness of MDA-MB-231 cell via CCL20 production

“…In addition, CCL20 also promotes tumor cell invasion by upregulation of MMP9 in pancreatic cancer cells (22), increases proliferation of colorectal cancer cells (23), and stimulates osteoblast cell growth (24). Thus, we examined the effect of CCL20 on breast cancer cells.…”