Ling Qin, Ph.D.

Description of Research Expertise

Area of Expertise:

Bone metabolism, stem cell biology, growth plate development, cancer bone metastasis, and signal transduction


Area of Special Interest:

The adult human skeleton continuously undergoes remodeling, namely, being resorbed by osteoclasts and renewed by osteoblasts. The maintenance of the skeleton requires the coordinated activities and constant generation of these cells. Disruption of this coordination underlies many bone diseases, such as osteoporosis and cancer-associated bone loss. These diseases cause great morbidity and mortality in the elderly and bone metastasized cancer patients and therefore are major public health problems worldwide. A variety of growth factors and hormones play important roles in bone metabolism. Our laboratory focuses on epidermal growth factor receptor (EGFR) and its ligands and uses a combination of molecular, biochemical, imaging and animal techniques to understand the molecular mechanisms of how this signaling pathway network regulates bone metabolism and skeletal development.

Ongoing research projects:

1. EGFR signaling in bone metabolism and parathyroid hormone (PTH) treatment of osteoporosis.
PTH, a major mediator of calcium homeostasis and bone remodeling, is one of the most effective drugs for osteoporosis treatment. Intermittent administration of PTH greatly stimulates bone formation by acting through its receptor on osteoblasts. Our research identified that the expression of amphiregulin, an EGFR ligand, is rapidly and highly stimulated by PTH in osteoblastic cells. We have constructed transgenic and pharmacological mouse models with altered EGFR activity and demonstrated that osteoblastic EGFR signaling primarily plays an anabolic role in bone metabolism. This project attempts to understand the physiological function of EGFR signaling in bone and whether this signaling pathway mediates PTH’s anabolic actions.

2. EGFR signaling in the proliferation, differentiation, apoptosis, and migration of bone marrow mesenchymal stem cell (MSCs).
Bone marrow MSCs are adult stem cells residing in the bone marrow cavity. They are multipotent progenitors for osteoblasts, adipocytes, and chondrocytes in bone. Numerous studies also suggest that these cells can give rise to muscle fibers, hepatocytes, endothelial cells and even neural tissue in vitro. Hence, they are a promising tool for regenerative medicine and gene therapy. Emerging results suggest that EGFR signaling stimulates MSC proliferation but can have conflicting effects on the cells’ multidifferentiation. Interestingly, our research identified EGFR ligands as potent survival and chemotactic factors for MSCs. The goal of this project is to delineate the function of EGFR signaling in the proliferation, multidifferentiation, apoptosis and migration of MSCs. This research will also provide interesting insight into whether EGFR ligands could be used as one of the substitutes for serum in ex vivo MSC expansion, which will be useful for stem cell transplantation.

3. EGFR signaling in cancer bone metastases.
Bone is the preferred metastasis site for many cancer cells. For example, breast cancer metastasizes to bone in greater than 80% of patients with advanced disease and leads to bone pain, fractures, hypercalcemia, and/or nerve compression. In the past several decades, enormous efforts have been focused on identifying tumor-derived factors that modify bone structures but yet the incomplete understanding of the underlying mechanism hinders the development of effective therapies that would help breast cancer patients. Using a coculture system containing bone marrow macrophage and osteoblastic cells, we found that EGFR ligands stimulate osteoclastogenesis via acting on osteoblastic cells. We are currently testing the hypothesis that tumor-derived EGFR ligands contribute to osteolytic lesions caused by cancer bone metastasis. Since several anti-EGFR agents are currently drugs for cancer treatment, this project will not only reveal a possible mechanism for cancer bone metastases, but also have important clinical implications.

4. EGFR signaling in endochondral ossification.
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 young growing rats treated with EGFR-specific inhibitors developed profound defects in growth plate cartilage characterized by epiphyseal growth plate thickening and massive accumulation of hypertrophic chondrocytes. This phenotype is chondrocyte-dependent because a mouse model of cartilage-specific EGFR inactivation exhibited a similar phenotype of hypertrophic cartilage enlargement. This project will investigate the mechanisms of EGFR signaling-induced extracellular matrix degradation in the cartilage and successfully accomplishing it will achieve a better management of diseases associated with growth defects, such as chondrodysplasia, retarded growth and reduced final height, and degenerative cartilage diseases, such as osteoarthritis.