Abstract
BackgroundIt is well-documented that both chemokine (C-C motif) ligand 19 (CCL19) and 21 (CCL21) mediate cell migration and angiogenesis in many diseases. However, these ligands’ precise pathological role in ankylosing spondylitis (AS) has not been elucidated. The objective of this study was to examine the expression of CCL19 and CCL21 (CCL19/CCL21) in AS hip ligament tissue (LT) and determine their pathological functions.MethodsThe expression levels of CCL19, CCL21 and their receptor CCR7 in AS (n = 31) and osteoarthritis (OA, n = 21) LT were analyzed via real-time polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC). The expression of CCL19, CCL21 and CCR7 in AS ligament fibroblasts was also detected. The proliferation of ligament fibroblasts was measured via a cell counting kit-8 (CCK8) assay after exogenous CCL19/CCL21 treatment. Additionally, the role of CCL19/CCL21 in osteogenesis was evaluated via RT-PCR and enzyme-linked immunosorbent assay (ELISA) in individual AS fibroblast cultures. Furthermore, the expression of the bone markers alkaline phosphatase (ALP), osteocalcin (OCN), collagenase I (COL1), integrin-binding sialoprotein (IBSP) and the key regulators runt-related transcription factor-2 (Runx-2) and osterix were investigated. Moreover, the CCL19/CCL21 levels in serum and LT were measured via ELISA.ResultsThe mRNA levels of CCL19/CCL21 in AS hip LT were significantly higher than that in OA LT, and IHC analysis revealed a similar result. Exogenous CCL19/CCL21 treatment did not affect the proliferation of ligament fibroblasts but significantly up-regulated the expression of bone markers, including ALP and OCN, and the key regulators Runx-2 and osterix. In addition, the serum levels of CCL19/CCL21 were apparently elevated in AS patients compared to healthy controls (HC), and the expression of the two chemokines correlated significantly in AS patients.ConclusionsCCL19 and CCL21, two chemokines displaying significantly associated expression in serum, indicating a synergistic effect on AS pathogenesis, may function as promoters of ligament ossification in AS patients.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2474-15-316) contains supplementary material, which is available to authorized users.
Highlights
It is well-documented that both chemokine (C-C motif) ligand 19 (CCL19) and 21 (CCL21) mediate cell migration and angiogenesis in many diseases
We found that Chemokine ligand 19 (CCL19)/Chemokine ligand 21 (CCL21) were primarily expressed on cells surrounding the capillaries, which likely corresponds to vascular endothelial cells, indicating a more important role in angiogenesis and migration of cells such as macrophages and dendritic cells
Previous studies found a proangiogenic effect of CCL19/CCL21 via the induction of secretion of vascular endothelial growth factor (VEGF) and angiotensin I (Ang-I) in fibroblasts [16]
Summary
It is well-documented that both chemokine (C-C motif) ligand 19 (CCL19) and 21 (CCL21) mediate cell migration and angiogenesis in many diseases. These ligands’ precise pathological role in ankylosing spondylitis (AS) has not been elucidated. Fibroblasts are the most numerous connective tissue cells in enthesis or ligament tissue (LT) and are reported to be associated with heterotopic ossification (HO) in LT [4,5]. Studies have demonstrated that CCR7 is responsible for the migration of T cells into inflamed tissues and T-cell egress from these tissues via the afferent lymph under inflammatory conditions [10] and that CCR7 knockout attenuates the development of diseases such as coronary sclerosis [11]. CCR7 signaling is considered to mediate both angiogenesis and tumor metastasis in different tumor microenvironments [12,13,14]
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