Drugs currently used to prevent bone loss—such as bisphosphonates and denosumab—are costly and may cause serious complications, raising socioeconomic and clinical questions about their long-term use, according to Francis Young-In Lee, MD, PhD, the Robert E. Carroll and Jane Chace Carroll Laboratories Professor at Columbia University. Through Dr. Lee's pioneering studies of inflammation and bone loss, he and his colleagues have shed light on the common inflammatory pathways that lead to the breakdown of bone in various clinical settings, such as infection, skeletal metastases, pathological fractures, implant loosening, and primary bone tumors, with the goal of enabling the development of novel forms of targeted, mechanism-based therapies for enhancing bone quality in patients with osteolytic conditions (Fig. 1).
Throughout 2 decades of study, Dr. Lee has focused on examining the inflammatory signaling pathways in osteoprogenitor cells—cells that, as Dr. Lee notes, have "two faces." While they are known for playing an important part in bone formation (osteogenesis), they are also involved in the breakdown of bone tissue (osteoclastogenesis) and bone resorption (Fig. 2).
"We have provided ample evidence for a competent innate immune inflammatory function of osteoprogenitors and regulatory pathways in the context of toxins, biomaterial particulate debris, excessive mechanical loading, primary bone tumors, infection, metastatic bone cancers, and osteoclastogenesis," wrote Dr. Lee. "Further research on pharmacologic or molecular modulation of inflammatory pathways will provide more scientific insights and better clinical outcomes in the aforementioned disorders.
"Based on our work," Dr. Lee continued, "we may add a next-generation therapeutic repertoire for inflammatory bone disorders such as infection, osteolytic metastatic bone cancers, and implant loosening."
Dr. Lee received the 2016 Kappa Delta Ann Doner Vaughn Award for the paper summarizing this research, "Targeting of Innate Immune Inflammatory Pathways in Osteolytic Disorders."
Surgeon-driven translational research
As an orthopaedic surgeon, Dr. Lee has addressed these challenges while caring for patients with persistent bone infection or pathological fractures. According to Dr. Lee, ordinary osteogenic differentiation and bone formation occur when innate immune inflammatory signaling is not activated. However, in the presence of irritants such as wear particles, excessive mechanical loading, deregulated host neoplastic cells, or bacteria, osteoprogenitor cells function as innate immune cells producing osteoclastogenic cytokines.
In recent years, a great deal of research has been completed in tissue engineering, fracture healing, and developmental biology to augment the understanding of bone formation, noted Dr. Lee. Meanwhile, he and his fellow researchers have been conducting translational research using mechanistic experiments, human cells, and pathologic samples to obtain evidence supporting osteoprogenitors as innate immune inflammatory entities.
A cardinal sign of bone inflammation is osteoclastogenesis and bone resorption. The researchers found that osteoprogenitors became inflammatory cells when challenged with bacteria, toxins, wear particles, or cancer cells. Then, osteoprogenitor cells produced pro-inflammatory and pro-osteoclastogenic cytokines that resulted in an intense inflammatory response and dramatic osteoclastic bone resorption, even in the absence of T-cells and B-cells. Common clinical examples of this process are surgical site infection or implant infection.
"Methicillin-resistant Staphylococcus aureus (MRSA) is a major clinical concern these days," said Dr. Lee. "When osteoblasts are exposed to MRSA, many of them die. MRSA often invade the cell and reside inside the host cells."
Dr. Lee's team observed that such intracellular bacteria are very difficult to eliminate, and may proliferate at any time. Both dying and surviving osteoprogenitor cells became inflammatory and produced cytokines that destroyed bone and soft tissues in a sustained manner. During this inflammatory conversion of osteoprogenitor cells, a small group of specific signaling proteins such as extracellular kinase 1/2 (ERK 1/2) are activated.
According to Dr. Lee, bacteria, implant particles, or osteolytic metastatic cancer cells create inflammation, and then host cells, including osteoprogenitors, become inflammatory cells in a sustained way.
Patients with avian influenza or Ebola virus become severely ill or die due to cytokines that are produced by the host cells and subsequent inflammation, not the virus itself, noted Dr. Lee. Inflammation is a defensive mechanism, he added, but too much inflammation in a sustained manner is harmful to the host.
"Targeting a key central mediator for producing many different cytokines such as receptor activator of nuclear factor kappa-B ligand (RANKL), macrophage colony-stimulating factor (MCSF), interleukin (IL), and tumor necrosis factor (TNF) is more effective than blocking each cytokine," he explained.
Another intriguing observation relates to osteolytic metastatic bone cancers. When Dr. Lee compared many different breast cancer cell lines, he found that most aggressive bone-destructive breast cancer cells convert osteoprogenitors into inflammatory cells and use them to make bone-destroying cytokines.
"In an effort to develop a more bone-specific, antimicrobial/inflammatory strategy, we are currently validating bisphosphonate-nano-bubbles containing antibiotics and kinase inhibitors to maximize local infection control," Dr. Lee explained. "Our early data showed that bisphosphonate-nano-bubbles containing antibiotics definitely prevented bacterial adhesion and bactericidal effects."
According to Dr. Lee, two important subjects to consider in the development of the next generation of treatments for bone or implant infection include initial bactericidal treatments and subsequent modulation of sustained host inflammation responsible for tissue destruction.
Further study and clinical impact
The central message of Dr. Lee's body of work thus far is that "osteogenesis and osteoclastogenesis are not necessarily two separate events, because they are part of the two faces of osteoprogenitor cells."
In Dr. Lee's view, a number of opportunities exist for uncovering novel functions of known and newly discovered genes and proteins ultimate with the goal of translating those discoveries into therapeutics.
"We look forward to collaborating with scholars from the AAOS and the Orthopaedic Research Society (ORS) to unravel novel pathways and therapeutic agents," he said. "All my research ideas stem from unmet clinical needs and complications that I was not able to resolve with the currently available medical armamentarium in my clinical practice. How many times have we done repeated irrigation and débridements in patients with infection? Our professional organizations and academic institutions need to maintain a pool of orthopaedic surgeon translational researchers to develop new, scientifically proven therapeutic strategies in the era of personalized medicine."
Finally, Dr. Lee expressed his deep appreciation to the leadership and senior investigators of the AAOS, the ORS, and the Orthopaedic Research and Education Foundation who have mentored and guided orthopaedic surgeon translational researchers.
The Kappa Delta Ann Doner Vaughn Award will be presented during the Ceremonial Meeting of the AAOS Annual Meeting on Thursday, March 3, in the Chapin Theater at the Orange County Convention Center, West Building. Dr. Lee will present his award-winning paper on Sunday, March 6, as part of the ORS annual meeting. Dr. Lee's disclosure information can be accessed at www.aaos.org/disclosure
Jennie McKee is a senior science writer for AAOS Now. She can be reached at email@example.com
- Evidence suggests a competent innate immune inflammatory function of osteoprogenitors and regulatory pathways as they relate to toxins, biomaterial particulate debris, excessive mechanical loading, primary bone tumors, infection, metastatic bone cancers, and osteoclastogenesis.
- This research on targeting common inflammatory pathways may lead to novel therapies and better clinical outcomes for patients with osteolytic conditions.
- Additional research on pharmacologic or molecular modulation of inflammatory pathways is needed to obtain more scientific insights into the treatment of inflammatory bone disorders in the era of personalized or precision medicine.
- Dr. Lee recommends maintaining a pool of orthopaedic surgeon translational researchers who will bring innovative concepts and technologies to clinics.