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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. 

Previous work in the lab mainly focused on the role of HS in regulating differentiation of osteoclasts, or osteoclastogenesis. In particular, we have studied 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. 

Currently, the lab focuses on understanding the role of HS in regulating cathepsin K (CtsK) biology. CtsK is a potent collagenase secreted by osteoclasts and is predominantly responsible for bone matrix degradation. Although CtsK is known to bind HS with high affinity, how HS regulates the biological functions of CtsK remains completely unknown..  We hypothesis that heparan sulfate regulates the activity and localization of CtsK, and that CtsK activity can be manipulated by targeting its HS-binding site. By using a combination of biophysical, biochemical, physiological and pharmacological methods, we aim to better understand the role of HS-CtsK interact in bone remodeling and hopefully develop HS-based therapeutics that target the collagenase activity of CtsK. 

Moving forward, we are actively developing new projects trying to delineate the roles of HS in osteoclast and osteoblast biology. 

Key publications on bone remodeling:

  1. 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 (2022);11:e71403 DOI: 10.7554/eLife.71403.

  2. Miaomiao Li & Ding Xu (2020). Antiresorptive activity of osteoprotegerin requires an intact heparan sulfate-binding site. PNAS. doi: 10.1073/pnas.2005859117. PMID: 32636266

  3. 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.

  4. 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.

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