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Joseph A. Tamasi
M.A., The College of New Jersey - 1983
Thesis Advisor: Nicola C. Partridge, Ph.D.
Graduate Program in Physiology and Integrative Biology
School of Public Health
Friday, May 6, 2011
Parathyroid hormone (PTH) is the major hormone regulating calcium homeostasis, but it also has a significant role as an anabolic hormone in bone when administered by intermittent injection. The mechanisms for the bone anabolic effect of PTH are not understood. However, it has been established that the anabolic effects of PTH require osteoclast activity. PTH acts through a single receptor on the osteoblast to regulate many known genes. Previous microarray studies in our laboratory have shown that the most highly regulated gene, monocyte chemoattractant protein-1 (MCP-1), is rapidly and transiently induced when hPTH(1-34) is injected intermittently in rats for 14 days. Through further in vivo studies, rats treated with hPTH(1-34) for 14 days showed a significant increase in serum MCP-1 levels 2 h after the last PTH injection compared to basal levels obtained prior to the last injection. Furthermore, the increase in serum MCP-1 is dependent on dose and duration of treatment. Increased MCP-1 expression shown by immunohistochemistry is evident in trabecular osteoblasts by the second daily PTH injection with peak staining occurring between 3 and 7 days of treatment. Male and female MCP-1 -/- mice injected daily with 80 ƒÝg/kg hPTH(1-34) for 6 weeks showed significantly reduced anabolic effects of PTH compared to wild type mice as measured by pQCT and microCT. PTH treated MCP-1 -/- mice have significantly less trabecular bone mineral density (BMD) than the corresponding PTH-treated wild type mice. Trabecular bone volume (BV/TV) increased in PTH-treated wild type mice with a corresponding increase in trabecular thickness (Tb.Th), however no increase in BV/TV or Tb.Th was observed in the PTH treated MCP-1 -/- mice. In contrast the absence of MCP-1 had little effect in the cortical compartment. Cortical BMD and cortical thickness increased in PTH treated MCP-1 -/- mice. Histomorphometric analysis revealed that the 2 fold increase in osteoclast surface and osteoclast number observed with intermittent PTH treatment in wild type mice was completely eliminated in MCP-1 -/- mice. Consequently, the lack of osteoclast activity in MCP-1 -/- mice was paralleled by a significant reduction in osteoid surface, mineralizing surface and bone formation rate compared to PTH treated wild type mice. These results demonstrate that osteoblastic MCP-1 expression is essential for the anabolic effects of PTH on bone.