CCL20 chemokine induces both osteoblast proliferation and osteoclast differentiation: Increased levels of CCL20 are expressed in subchondral bone tissue of rheumatoid arthritis patients.
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.
Lisignoli
Gina
G
Laboratorio di Immunologia e Genetica, Istituti Ortopedici Rizzoli, Bologna, Italy. labimge@alma.unibo.it
Piacentini
Anna
A
Cristino
Sandra
S
Grassi
Francesco
F
Cavallo
Carola
C
Cattini
Luca
L
Tonnarelli
Beatrice
B
Manferdini
Cristina
C
Facchini
Andrea
A
D000368:Aged; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology*; D001706:Biopsy; D016723:Bone Remodeling; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D054418:Chemokine CCL20; D019742:Chemokines, CC / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D006706:Homeostasis; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology*; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D054399:Receptors, CCR6; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism
C108355:CCL20 protein, human; C106311:CCR6 protein, human; D054418:Chemokine CCL20; D019742:Chemokines, CC; D019402:Macrophage Inflammatory Proteins; D053245:RANK Ligand; D054399:Receptors, CCR6; D019707:Receptors, Chemokine; C505688:TNFSF11 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D020780:Matrix Metalloproteinase 9