Heparan sulfate in Bone remodeling
One main focus of the lab is to understand the pathophysiological role of HS in bone remodeling. Bone remodeling is a life-long process controlled by the balanced activity of the bone-forming osteoblasts and the bone-resorbing osteoclasts. When this balance is compromised, bone density and strength will be impaired, which leads to a number of highly prevalent diseases such as osteoporosis, rheumatoid arthritis and periodontitis. As HS is expressed by both osteoblasts and osteoclasts, we believe that HS plays roles in both bone formation and bone resorption. In addition, as a major component of extracellular matrix, it is highly likely that HS also regulates the crosstalk between osteoblasts and osteoclasts.
Current work in the lab mainly focuses on the role of HS in regulating differentiation of osteoclasts, or osteoclastogenesis. In particular, we are studying a major negative regulator of osteoclastogenesis called osteoprotegerin (OPG). OPG is a high affinity HS-binding protein and works as a decoy receptor to neutralize the activity of the essential osteoclastogenic factor RANKL. Over the past 5 years, by using a highly multidisciplinary approach, which spans structural, cellular and animal model studies, we have established that HS is absolutely required for the anti-RANKL activity of OPG, which represents the very first defined role of HS in bone remodeling.
Moving forward, we are actively developing new projects trying to delineate the roles of HS in osteoclast activity, osteoblast differentiation and activity, and osteocyte crosstalk with osteoblasts and osteocytes.
Key publications on bone remodeling:
Miaomiao Li, Chih Yean Ong, Christophe J Langouët-Astrié, Lisi Tan, Ashwni Verma, Yimu Yang, Xiaoxiao Zhang, Dhaval K. Shah, Eric P. Schmidt and Ding Xu (2022). Heparan Sulfate-dependent RAGE oligomerization is indispensable for pathophysiological functions of RAGE. eLife. In press
Miaomiao Li & Ding Xu (2020). Antiresorptive activity of osteoprotegerin requires an intact heparan sulfate-binding site. PNAS. doi: 10.1073/pnas.2005859117. PMID: 32636266
Yiming Xiao, Miaomiao Li, Rinzhi Larocque, Fuming Zhang, Anju Malhotra, Jianle Chen, Robert J. Linhardt, Lars Konermann, and Ding Xu (2018). Dimerization Interface of Osteoprotegerin Revealed by Hydrogen-deuterium Exchange Mass Spectrometry. J Biol Chem 293 (45), 17523-17535. PMID: 30254073.
Miaomiao Li, Shuying Yang, Ding Xu* (2016). Heparan Sulfate Regulates the Structure and Function of Osteoprotegerin in Osteoclastogenesis . J Biol Chem 291 (46):24160-24171. PMID: 27697839.