The Pathophysiology of Bone Loss

Research Summary

Research topic 1: Investigation of the role that cytokines and chemokines play in inflammatory osteolysis associated with giant cell bone tumors

Research results 1: Determined that a specific regulatory protein, stromal cell-derived factor-1 (SDF-1), is the primary signaling agent controlling destructive cell activity leading to bone loss associated with giant cell tumors

Patient care application of results 1: A deeper understanding of the biology of bone loss prompts new questions about how osteolysis is triggered and warrants strategies for intervention

Simplified patient care application 1: A better understanding of bone biology will hasten the discovery of new pathways to protect bone health, reduce pain and preserve mobility for patients with giant cell tumors

Research topic 2: The body’s response to implant debris was studied at the cellular level by examining the potential roles that nuclear factor of activated T cells (NFAT) and calcineurin, the signaling protein that activates NFAT, play in producing cytokines related to bone loss

Research results 2: Determined that wear debris triggers calcineurin multidimensionally, impacting both cell formation and destruction

Patient care application of results 2: Provided knowledge that will help identify therapeutic targets and pharmaceutical interventions for bone loss associated with implant wear, bone tumors and other bone-destroying conditions, including cancer and osteoporosis

Simplified patient care application 2: Provided knowledge that will help develop disease-specific drug therapies that will fight bone loss at the cellular level

The Pathophysiology of Bone Loss

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

Jay D. Lenn

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

Three grants from the Orthopaedic Research and Education Foundation (OREF) have helped Dr. Lee, professor with tenure, Orthopaedic Surgery at Columbia University, New York, N.Y., 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

A 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 that have generated further questions about the mechanisms of osteolysis and established a new direction for future research.

Retracing steps to joint loosening

Dr. Lee received a 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 osteolyis-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 that:

• 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.”

 Building a Career: Clinician Scientist 101

“As a third-year resident in 1995, I applied for an OREF Resident Research Grant,” said Francis Y. Lee, MD, PhD, professor with tenure, Orthopaedic Surgery at Columbia University, New York, N.Y. “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. So even the application process was a great educational opportunity.”

He received the resident grant, which funded research on fracture healing. Although this is no longer the focus of his research, Dr. Lee said, the grant was a critical step in establishing his career.

“It was a relatively small award of $15,000, but 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 mentor-mentee relationship with Thomas A. Einhorn, MD, who was already a prominent clinician scientist at that time. Moreover, between being awarded the OREF resident grant and later OREF Research and Career Development grants, Dr. Lee received an AAOS/OREF Clinician Scientist Traveling Fellowship—a program that paired new investigators with seasoned mentors for guidance and collaboration, and covered travel expenses for site visits.

Dr. Lee said, “By interacting with successful clinician scholars, I was able to acquire the skills, knowledge, and mental discipline needed to apply for NIH grants.” According to Dr. Lee, this resulted in 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.”

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 about the importance of translational research,” said Dr. Lee. “He provided both professional and emotional support in my own career as a clinician, researcher, and leader.”

Dr. Lee views his own translational research as an integral component of his work as an orthopaedic surgeon. “I always try to treat the patient as a whole person, not only considering the patient’s physical condition, but also the emotional, career, and family factors that are all so relevant to a healthy recovery. This is the foundation for comprehensive and compassionate patient care.”