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Francis Y. Lee, MD, PhD
Courtesy of Francis Y. Lee, MD, PhD

AAOS Now

Published 5/1/2013
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Jay D. Lenn

The Pathophysiology of Bone Loss

OREF grants help clinician scientist on the road to cell-based therapies

Over the course of his more than 20-year career, Francis Y. Lee, MD, PhD, found his passion in pursuing noninvasive interventions to treat osteolysis.

Two grants from the Orthopaedic Research and Education Foundation (OREF)—a Research Grant in 2004, and a Career Development Grant in 2006—have helped Dr. Lee, professor with tenure, orthopaedic surgery at Columbia University, New York, to advance his research on the molecular mechanisms of osteoclasts, the culprits behind osteoporosis, joint implant loosening, tumor-associated bone loss, and other disorders.

Tumor-associated bone loss
The 2004 OREF Research Grant supported Dr. Lee’s investigation of factors regulating osteolysis associated with giant cell tumors (GCTs). In this study, Dr. Lee and his colleagues hypothesized that the primary signaling agent mediating osteolysis was a regulatory chemokine secreted by GCT stromal cells. They demonstrated that this regulatory protein, called stromal cell-derived factor-1 (SDF-1), recruits the precursor cells of osteoclasts, enhances precursor cell survival, and promotes osteoclastogenesis.

In addition to providing valuable insight into the biology of bone loss, this study laid a solid foundation in molecular experimental models. Since then, these models have generated additional questions about the mechanisms of osteolysis and established a new direction for future research.

Retracing steps to joint loosening
Dr. Lee received the 2006 OREF Career Development Grant for his investigation of mechanisms linking implant debris and osteolysis-related joint loosening. The loosening of bone implants is associated with inflammatory osteolysis. The microscopic debris produced from the normal wear on an artificial joint is understood to be the primary trigger of this bone loss. Between the creation of debris and osteolysis-induced implant loosening is a complex series of molecular and cellular events.

Dr. Lee and his colleagues focused on the potential role of a transcription factor called nuclear factor of activated T cells (NFAT), as well as calcineurin, the signaling protein that activates NFAT. They tested the hypothesis that wear debris triggers the calcineurin/NFAT axis, leading to the production of several osteolysis-related cytokines.

The team found these cytokines are active not only in regulating inflammation but also in stimulating and enhancing osteoclast production. In a set of three experiments focusing on a transcription factor subtype called NFATc1, Dr. Lee’s group demonstrated the following:

  • Wear debris triggers the calcineurin/NFATc1 axis in osteoblasts—cells responsible for bone formation—which are known to produce pro-osteoclastogenic cytokines.
  • Wear debris triggers the calcineurin/NFATc1 axis in cells that serve as precursors to osteoblast cells.
  • The calcineurin/NFATc1 axis mediated osteolysis in a mouse model of implant wear debris.

These were significant findings that prompted further questions, which are still being investigated. Dr. Lee said, “This study provided the most critical preliminary data for two National Institutes of Health (NIH) grants.” He has received and renewed two NIH R01 grants (2007–2018) and noted that the growing body of knowledge about the mechanisms of osteolysis is enabling researchers to identify therapeutic targets and test potential pharmaceutical interventions, not only for wear debris-induced bone loss, but also for rheumatoid arthritis, bone tumors, metastatic bone cancers, and osteoporosis.

“This translational research,” said Dr. Lee, “is bridging the gap between basic science and unmet clinical needs. When there is no available method of treating difficult conditions, we need to discover new therapeutic tools and be willing to change the way we practice.”

Jay D. Lenn is a contributing writer for OREF and can be reached at communications@oref.org

Building a Career: Clinician Scientist 101
“As a third-year resident in 1995, I applied for an OREF Resident Research Grant,” said Dr. Lee. “I had no experience in grant writing, didn’t understand the format, and wasn’t sure what content to include. But I started to build a network with teachers and peers to learn about the process.”

Although it was a relatively small award, Dr. Lee says the resident grant was a critical step in establishing his career.”It was meaningful that OREF was willing to invest in me as a scientist. I was able to do research, present my work, and publish a paper. That first OREF grant really formed a solid foundation to build on, and OREF was crucial in my development as a clinician scholar by providing funding as well as mentorship opportunities.”

After receiving the resident grant, Dr. Lee established a mentoring relationship with Thomas A. Einhorn, MD, a prominent clinician scientist. Dr. Lee has since also received an AAOS/OREF Clinician Scientist Traveling Fellowship—a program that pairs new investigators with seasoned mentors. As a result of this support, he has received a Department of Defense grant and two NIH R01 grants, which were recently renewed.

“Federal grants and publications in high-impact journals led me to become a tenured professor at Columbia University, and I have shared my personal experiences with junior investigators through the AAOS/OREF/ORS Clinician Scholar Development Program and Grant Writing Workshop,” said Dr. Lee.

When Dr. Lee took a position at Columbia University in 1999, he began working with Louis U. Bigliani, MD, whose research on shoulder treatment spans more than 30 years. “Dr. Bigliani shared with me his vision of the importance of translational research,” said Dr. Lee, who now makes translational research an integral component of his work as an orthopaedic surgeon.