Pathological bone destruction.
Osteoclasts are bone resorbing cells responsible for physiological bone homeostasis and the pathological bone loss and destruction that can be found in diseases such as rheumatoid arthritis, osteolysis (implant loosening that leads to failure after joint replacement), bone metastasis, and osteoporosis. Our laboratory focuses on investigating the critical molecules and pathways that control bone loss and abnormalities for these devastating conditions, and has successfully inhibited bone erosion in preclinical models by targeting these pathways. We believe that understanding the mechanism of osteoclast differentiation is of great therapeutic importance for nearly all forms of metabolic bone disease.
Key research interests.
1) Understanding the metabolic reprogramming and epigenetic regulation of osteoclast differentiation in physiological and pathologic conditions.
2) Identifying novel regulators of osteoclastogenesis and biomarkers for osteoporosis.
3) Testing whether therapeutic targeting of these novel regulators represents a potential treatment for inflammatory and metabolic bone diseases.
Key implications.
Our studies will allow us to identify novel molecules and pathways that can be regulated as part of new strategies for suppressing osteoclastogenesis and pathologic bone resorption in human inflammatory diseases such as RA.
Select images courtesy of Alan Boyde and Dr. Alison Gartland.
Current projects.
Basic research.
Proteolysis pathways by ADAM17/TACE (TNF a-converting enzyme) in osteoclast differentiation.
Since drugs that inhibit TNF are extremely beneficial in the treatment of RA, TACE is considered to be a therapeutic target in RA. However, aside from processing TNF, TACE is also involved in the processing of several other important players in RA. We have found the TACE-mediated proteolysis pathway plays an important role in osteoclastogenesis and have identified a novel pathway regulated by TACE. We are currently testing the role of this new pathway in the pathogenesis of inflammatory bone diseases.
Epigenetic regulation of human osteoclast differentiation.
Another area of interest is understanding the epigenetic regulation and underlying epigenetic mechanisms in the early stage of human osteoclast differentiation. Epigenetic regulation is a key molecular mechanism by which environmental influences and cues are imprinted on DNA/chromatin, and determines patterns of gene expression, responses to environmental challenges, and disease causation and pathogenesis. Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Mutations or abnormal expression of chromatin regulators have been identified in several cancers and have been shown to be a switch that transforms normal cells to disease-associated cells. Interestingly, a large number of these proteins are druggable, and many chromatin regulators are enzymes or ‘readers’ that can be targeted through conventional small molecule approaches. We have investigated the role of epigenetic regulation in osteoclasts and have demonstrated that targeting an epigenetic molecule in osteoclasts can be effective in suppressing the pathological bone resorption that occurs in inflammatory settings such RA. We will further expand our findings to identify various epigenetic targets and underlying mechanisms by which epigenetic molecules regulate osteoclastogenesis. We believe that our studies open up a new line of investigation in the understanding and therapeutic targeting of pathological bone resorption.
Elucidating the role of metabolic reprogramming during osteoclastogenesis.
The importance of metabolic reprogramming in osteoclast differentiation has been increasingly appreciated. However, the molecules that serve as key regulators of metabolic reprogramming in osteoclasts and the regulation of metabolic mechanisms during osteoclast differentiation remain unclear. We have shown that MYC is a central upstream regulator of metabolic reprogramming during osteoclastogenesis and how altered cellular metabolism impacts osteoclast regulation. Intriguingly, MYC governs many different metabolic pathways in osteoclasts in a temporal manner. Our studies provide a better understanding of the diverse roles of MYC in osteoclastogenesis that will not only advance our fundamental understanding of osteoclast biology, but will also facilitate the identification of effector molecule(s) downstream of MYC that may serve as novel therapeutic targets for the treatment of pathological bone resorption.
Translational research.
Developing a new biomarker for early detection of osteoporosis.
Osteoporosis is a metabolic bone disorder that compromises bone strength and leads to an increased risk of fracture. Skeletal fractures caused by osteoporosis lead to morbidity and an increased risk of mortality; such fractures are also associated with expensive care costs. Thus, osteoporosis represents a serious public health problem, and both early diagnosis and effective therapies for osteoporosis are urgently needed. However, current diagnostic methods are unsuitable for early detection of the risk of fracture, and available anti-resorptive drugs that are effective in inhibiting bone resorption have significant side effects. Therefore, we aim to develop early diagnostic biomarkers of osteoporosis or pathological bone loss. We have found a cellular biomarker that is closely related to osteoclast activity and bone quality in humans.
Identifying a risk factor for avascular necrosis (AVN).
Avascular necrosis (osteonecrosis) is defined by the death of bone tissue and is an underlying diagnosis of about 10% of hip replacement surgeries performed in the U.S. As a debilitating disease, AVN causes severe pain and compromised quality of life. The use of steroids is the most common cause of AVN, and our study focuses on steroid-induced AVN. Paradoxically, while some patients treated with chronic high dose steroids develop AVN, many others who receive doses of the same magnitude do not. This discrepancy suggests that there are underlying patient-specific factors that govern susceptibility to AVN in the setting of high dose steroids. However, the underlying mechanisms of the difference in susceptibility of steroid-induced AVN are unknown. In addition, strategies for the prevention and treatment of AVN are limited, with no effective therapy that can reverse conditions, primarily, because the pathogenesis of AVN is poorly understood. Thus, we aim to investigate the specific factors that determine an individual’s risk of developing AVN that can directly lead to the development of novel therapeutic strategies to prevent or halt the disease’s progression.