Intermittent parathyroid hormone (PTH) injection is one of the most effective anabolic treatments for osteoporosis because of its remarkable actions on bone formation. Osteoblasts are derived from mesenchymal progenitors, including mesenchymal stem cells (MSCs) and committed osteoprogenitors. Multiple mechanisms have been proposed to explain how PTH exerts its beneficial effects, but whether these effects include, or are mediated by, a stimulation of bone marrow mesenchymal progenitor activities, is not clear. Our new data support this mechanism by demonstrating the presence of a functionally distinct population of mesenchymal progenitors within the trabecular bone that are very responsive to PTH. PTH strongly stimulates the expression of amphiregulin, an epidermal growth factor receptor (EGFR) ligand, in osteoblasts and osteocytes. EGFR is highly expressed in mesenchymal progenitors and its activation stimulates proliferation, survival, and migration of these cells. Our preliminary data show that blocking EGFR activity in mice leads to defective bone formation and an osteopenic phenotype which are accompanied by a reduction in the number of mesenchymal progenitors. Interestingly, conditioned media from PTH-treated osteoblastic cells chemoattract mesenchymal progenitors in an amphiregulin-EGFR-dependent manner. Moreover, mice with deficient EGFR activity in osteoblast lineage cells have a poor anabolic response to PTH injection. These and other data lead to our central hypothesis that EGFR signaling is an essential regulator of bone marrow mesenchymal progenitors and mediates at least in part the anabolic effects of intermittent PTH administration. We will test our central hypothesis by pursuing the following aims: 1) investigate whether EGFR inactivation in MSCs inhibits bone formation and the anabolic response to PTH by assessing skeletal phenotypes of conditional EGFR knockout mice with a nestin promoter-driven inducible Cre with or without PTH treatment;2) elucidate whether EGFR plays a critical role in maintaining the bone marrow mesenchymal progenitor population under conditions of normal and PTH-induced bone formation. We will use animal models with deficient EGFR activity in mesenchymal progenitors at different stages of lineage commitment to investigate the relationship between EGFR activity and mesenchymal progenitor populations residing in different regions of the long bone. We will also use cell culture approaches to determine whether a group of transcription factors, Egrs, mediates and regulates EGFR-stimulated proliferation and survival of mesenchymal progenitors;3) determine whether EGFR signaling activated by PTH injection recruits mesenchymal progenitors toward the bone surface by using an in vivo transplantation approach, in which GFP-labeled mesenchymal progenitors can be visualized. Completion of these three aims will enable us to determine for the first time the role of EGFR in bone formation and the anabolic response of bone to the osteoporosis therapy PTH. Long-term, we seek to determine whether we can target EGFR signaling as a novel anabolic strategy to treat osteoporosis and other bone-related diseases.

Public Health Relevance

Intermittent parathyroid hormone (PTH) injection is one of the most effective anabolic treatments for osteoporosis-related bone diseases. This project will determine the novel role of epidermal growth factor receptor (EGFR) in bone formation and in controlling the size and migration of mesenchymal progenitors under normal and PTH treatment conditions. Information garnered from these studies will be important for optimizing the current osteoporosis treatment, designing novel therapeutic strategies to treat and prevent bone diseases, and advancing our current knowledge of stem cells.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Skeletal Biology Development and Disease Study Section (SBDD)
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Malozowski, Saul N
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University of Pennsylvania
Schools of Medicine
United States
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