Skeletal Biology and Regulation Published: 11 November 2019
Monocyte Chemoattractant Protein-1 (MCP-1/CCL2) Drives Activation of Bone Remodelling and Skeletal Metastasis
Abstract
Purpose of Review
The purpose of this review is to explore the role of monocyte chemoattractant protein-1 (MCP-1 or CCL2) in the processes that underpin bone remodelling, particularly the action of osteoblasts and osteoclasts, and its role in the development and metastasis of cancers that target the bone.
Recent Findings
MCP-1 is a key mediator of osteoclastogenesis, being the highest induced gene during intermittent treatment with parathyroid hormone (iPTH), but also regulates catabolic effects of continuous PTH on bone including monocyte and macrophage recruitment, osteoclast formation and bone resorption. In concert with PTH-related protein (PTHrP), MCP-1 mediates the interaction between tumour-derived factors and host-derived chemokines to promote skeletal metastasis. In breast and prostate cancers, an osteolytic cascade is driven by tumour cell–derived PTHrP that upregulates MCP-1 in osteoblastic cells. This relationship between PTHrP and osteoblastic expression of MCP-1 may drive the colonisation of disseminated breast cancer cells in the bone.
Summary
There is mounting evidence to suggest a pivotal role of MCP-1 in many diseases and an important role in the establishment of comorbidities. Coupled with its role in bone remodelling and the regulation of bone turnover, there is the potential for pathological relationships between bone disorders and bone-related cancers driven by MCP-1. MCP-1’s role in bone remodelling and bone-related cancers highlights its potential as a novel anti-resorptive and anti-metastatic target.
Introduction
Monocyte chemoattractant protein-1 (MCP-1) is a member of the CC-motif chemokine family (as CCL2); a large group of cell signalling molecules and cognate receptors. MCP-1 was the first discovered human chemokine and is well-known as a potent chemotactic factor for monocytes [1,2,3]. It is produced by a number of different cell types, including endothelial, epithelial, smooth muscle, mesangial, astrocytic, monocytic, microglial and fibroblastic. MCP-1 is either constitutively produced or induced subsequent to oxidative stress, specific cytokine activity or specific growth factor activity [1]. MCP-1 mediates its action through CC receptors (CCRs), predominantly CCR2. Dissimilarly to MCP-1, CCR2 is not so universally expressed, with its expression mostly restricted to vascular smooth muscle cells, mononuclear cells, monocytes and activated natural killer (NK) cells [1]. One of the peculiar aspects of CC chemokine biology is that a high degree of cross-talk exists between receptors and chemokines. Chemokines act as both homodimers and as heterodimers with structurally similar chemokines—a particular chemokine may interact with other chemokines and with several primary receptors and, if at a high enough concentration, may possibly interact with other, atypical receptors [4]. Chemokines also have affinity for extracellular matrix molecules, such as glycosaminoglycans (GAGs), which alters the effective concentration.
A further characteristic of chemokine biology is the proteolytic processing of chemokines [4], which can produce dominant-negative forms and, in some cases, more potent forms. A dominant-negative form of MCP-1 exists and is referred to as 7ND; MCP-1 with 7 amino acids truncated from the N-terminus. It completely inhibits the action of MCP-1 and has gained traction as a useful investigative tool and as a potential novel therapeutic [5•, 6, 7]. Despite such functional complexity in chemokine biochemistry, inflammatory chemokines usually elicit strong cellular responses—MCP-1 has been widely accepted as a profound inflammatory mediator, having both pro-inflammatory and anti-inflammatory roles [1]; consequently, MCP-1 has been the subject of many studies. There is mounting evidence for the involvement of MCP-1 in bone remodelling as a critical mediator, the pathogenesis of particular bone diseases and the metastasis of particular cancers to the bone; the focal point of this review.
Monocyte Chemoattractant Protein-1 (MCP-1/CCL2) Drives Activation of Bone Remodelling and Skeletal Metastasis | SpringerLink
https://link.springer.com/article/10.1007/s11914-019-00545-7
Glycyrrhizin affects monocyte migration and apoptosis by blocking HMGB1 signaling
Department of Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
Monocytes serve an important role in systemic inflammation. High mobility group box‑1 protein (HMGB1) promotes recruitment and suppresses apoptosis in monocytes through the receptor for advanced glycation end products/ nuclear factor (NF)‑κB and toll‑like receptor 4/mitogen‑activated protein kinase (MAPK)/extracellular signal‑regulated kinase (ERK) signaling pathways. Glycyrrhizin (GL), an effective component of licorice, weakens the proinflammatory effect of HMGB1. The present study investigated the effect of GL on the migration and apoptosis of monocytes associated with HMGB1 signaling. THP‑1 cells were used to evaluate the behavior of monocytes in response to GL treatment, and the downstream pathways were investigated. GL suppressed HMGB1‑induced monocyte migration and increased HMGB1‑inhibited monocyte apoptosis. GL inhibited the activation of the NF‑κB and MAPK/ERK signaling pathways induced by HMGB1 and decreased the expression of monocyte chemoattractant protein‑1 (MCP‑1) and myeloid cell leukemia 1 (Mcl‑1). Taken together, the results indicated that GL may suppress the migration of monocytes and induce apoptosis to reduce systemic inflammation by blocking downstream NF‑κB/MCP‑1 and MAPK/ERK/Mcl‑1 signaling pathways.Glycyrrhizin affects monocyte migration and apoptosis by blocking HMGB1 signaling
https://www.spandidos-publications.com/10.3892/mmr.2018.8598
Toxicol Ind Health. 2018 Jan;
MCP-1 produced by keratinocytes is associated with leucocyte recruitment during elicitation of nickel-induced occupational allergic contact dermatitis
Abstract
To investigate the expression profile of monocyte chemoattractant peptide-1 (MCP-1) by keratinocytes after nickel exposure and to identify its role for leucocyte migration during nickel-induced occupational allergic contact dermatitis (OACD), 26 workers diagnosed with nickel-induced OACD were enrolled. Skin biopsies from the positive nickel-challenged sites at different time points were assessed by immunohistochemistry (IHC) for MCP-1, CD68, CD45RO, and in situ hybridization (ISH) for MCP-1, using chronic periumbilical dermititis as controls. The expressions of MCP-1 in HaCaT cell culture after nickel treatment were quantified by enzyme-linked immunosorbent assay. The results showed that at positive nickel-challenged sites, strong expressions of MCP-1, both messenger RNA (mRNA) and protein, were detected in the basal keratinocytes during the early phase (24-48 h after nickel application), paralleled by the recruitment of CD68+ and CD45RO+ cells to the skin compartments. The expressions of MCP-1 declined gradually in the late phase (72-96 h after nickel application). Treatment with nickel sulfate at noncytotoxic concentrations (0.01-100 µM) induced a concentration-related elevation of MCP-1 expression by HaCaT cells compared to the untreated cells. The data indicated that a temporal expression pattern of MCP-1 produced by keratinocytes after nickel exposure was involved in the complex process of mononuclear cell infiltration during elicitation of nickel-induced OACD. Targeting MCP-1 might be a potential therapeutic strategy for OACD.
Keywords: HaCaT keratinocyte; Monocyte chemoattractant peptide-1; leucocyte migration; nickel; occupational allergic contact dermatitis.MCP-1 produced by keratinocytes is associated with leucocyte recruitment during elicitation of nickel-induced occupational allergic contact dermatitis - PubMed
https://pubmed.ncbi.nlm.nih.gov/29132256/