Ongoing Research at Qin Laboratory
The human skeleton is a dynamic tissue, constantly undergoing remodeling through coupled activities of two cells: the bone-resorbing osteoclasts and the bone-forming osteoblasts. A shift in the balance of these two actions toward resorption leads to osteoporosis, a silent disease characterized by excessive bone loss and micro-architectural deterioration of bone tissue leading to bone fragility and fracture. Osteoblasts are derived from mesenchymal progenitors, including mesenchymal stem cells (MSCs) and committed osteoprogenitors. Convincing evidence suggests that there are decreases in the number and proliferative capacity and increases in senescence and apoptosis of mesenchymal progenitors in aging and osteoporotic populations. Bone formation by osteoblast lineage cells is controlled by a variety of growth factors and hormones. Our laboratory is interested in understanding their downstream signaling pathways that regulate the biology of bone formation, with a special focus on parathyroid hormone (PTH1-34, teriparatide), the only FDA-approved anabolic treatment for osteoporosis.
One area of our interest is addressing the essential role of epidermal growth factor receptor (EGFR) in regulating bone marrow mesenchymal progenitor pool and mediating the effect of PTH on bone formation. We have demonstrated that amphiregulin, an EGFR ligand, is one of the highest PTH-stimulated genes in osteoblasts and osteocytes. Activation of EGFR signaling in mesenchymal progenitors stimulates their proliferation, survival, and migration. 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. More importantly, mice deficient in osteoblast lineage EGFR activity have a poor anabolic response to PTH-induced bone formation. We utilize transgenic and pharmacological mouse models in combination with molecular, biochemical, and imaging assays for these studies.
Our second line of interest is investigating molecular mechanisms by which PTH treatment rescues bone loss and osteoporosis induced by radiotherapy. Radiotherapy is often used to eliminate tumor cells but it has negative effects on neighboring normal tissues including bone, causing acute and chronic problems such as osteoradionecrosis, osteoporosis, and fractures. The primary radiation damage to bone is local tissue atrophy, characterized by loss of functional osteoblasts, marrow adiposity, and microvascular impairment. We found that daily injections of PTH1-34 largely prevents bone loss and deterioration of bone structure in irradiated rodent bone and that the major mechanism appears to be protection of mature osteoblasts and bone marrow mesenchymal progenitors. One interesting finding is that PTH is capable of promoting DNA double strand break (DSB) repair in irradiated osteoblasts and thus protecting osteoblasts from radiation-induced cell death. Innovative approaches, such as small animal radiation research platform (SARRP) that replicates the effects of focal radiation therapy, in vivo µCT imaging and longitudinal tracking of the same trabecular bone, and lineage tracing in genetically modified mouse models are used for this project.
The third area of interest is identifying and functionally characterizing a distinct mesenchymal progenitor population within bone marrow. Mesenchymal progenitor cells are traditionally isolated from the central region of long bones (central mesenchymal progenitors) and therefore, they are distant from bone surface. We have established a unique enzymatic digestion approach to isolate endosteal bone marrow cells that are close to bone surface and found that they contain a much higher frequency of mesenchymal progenitors than central bone marrow cells. We further demonstrated that endosteal mesenchymal progenitors have superior proliferation, greater immunosuppressive activity, and more responsiveness toward aging and PTH injection than central mesenchymal progenitors and therefore, represent a biologically important target for future mesenchymal stem cell studies. We are currently exploring the difference between these two populations of bone marrow mesenchymal progenitors with a special interest on their interactions with surrounding bone marrow environment.
Lastly, our group is interested in delineating the critical role of EGFR in regulating cartilage extraceullar matrix degradation. Growth plate development is a critical step in endochondral bone formation and longitudinal bone growth. This process, including chondrocyte proliferation, maturation, mineralization, matrix remodeling and transition from cartilage to bone, is tightly controlled by circulating systemic hormones and locally produced growth factors. We recently found that rodents, lacking of chondrogenic EGFR activity develop profound defects in growth plate cartilage characterized by epiphyseal growth plate thickening and massive accumulation of hypertrophic chondrocytes. The underlying mechanisms include stimulating the chondrogenic expression of matrix metalloproteinases (MMPs) and promoting osteoclastogenesis at the chondro-osseous junction. Study of this project will shed new light on growth defect diseases, such as chondrodysplasia, retarded growth and reduced final height, and degenerative cartilage diseases, such as osteoarthritis.