ECTS Abstracts (2015) 1 P190

Monocyte Chemotactic Protein-1 (MCP-1) is a Key Regulator of Osteoclastogenesis

Mark Forwood1, Gemma Diessel1, Andy Wu2, Ian Cassady1, Jelena Vider1, Wendy Kelly1 & Nigel Morrison1


1Griffith University, Gold Coast, Australia, 2Mater Research Institute, Brisbane, Australia.


Monocyte chemotactic protein-1 (MCP-1) plays a critical role in leukocyte recruitment and activation during inflammation, and has the highest level of gene induction in bone following anabolic PTH treatment1. MCP-1 is also specifically regulated during bone remodelling, activated to repair stress fracture2. We hypothesised that MCP-1 is a necessary regulator of osteoclastogenesis required for skeletal repair and remodelling. We used the ulnar stress fracture model, allowing scrutiny of focal remodelling with a known time course and precise anatomical location. Within 4 hours of stress fracture initiation, we observed significant increases in MCP-1 gene expression (P < 0.01), followed by increased serum levels within 24h (P < 0.05). To test our hypothesis, we used a plasmid DNA encoding a dominant negative mutant of MCP-1 (7ND) to specifically inhibit MCP-1 in vivo. Stress fracture was created in the right ulna of Wistar rats using cyclic end-loading. Unloaded animals were used as a control. 24 h prior to loading, 7ND plasmid vector, saline or empty vector control (pcDNA3.1), were injected in the thigh muscle to overexpress 7ND protein, effecting its secretion into systemic circulation. Rats were euthanised 4h (n=5/group) or 2 weeks (n=10/group) after loading for gene expression or histomorphometric analysis, respectively. MCP-1 gene expression (qPCR) increased significantly in untreated ulnae (saline and empty vector controls) within 4h of loading (P<0.001). This increase was abolished by 7ND treatment. At 2 weeks, there was a profound suppression of osteoclast number (61%), resorption area (50%) and new bone formation (60%) in basic multicellular units initiating remodelling of the stress fracture (P < 0.05). Conversely, 7ND treatment had no effect on formation of periosteal woven bone. MCP-1 is markedly upregulated by stress fracture, but also by intermittent PTH treatment. We therefore conclude that MCP-1 is a critical regulator of osteoclastogenesis during initiation events of bone remodelling.

Disclosure: The authors declared no competing interests. This work was supported by NHMRC Project 1049190.

References:

1. Li et al. (2007) JBC 282: 33086-33097.

2. Wu et al. (2013). Calcif Tissue Int 92:566–575.

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