Faculty Profile: Wentian Yang, M.D., Ph.D.

Wentian Yang, M.D., Ph.D.
Assistant Professor of Orthopaedics and Medicine (Research)
Orthopaedics
Work: +1 401-444-5956
Dr. Yang studies the regulation of development and homeostasis of bone and cartilage by protein tyrosine kinases (PTK) and phosphatases (PTP). One direction of his research focuses on how the viability, proliferation and chondrocytic differentiation of cartilage stem cells/progenitors are modulated by PTK and PTP. He also has a research interest in cellular signaling pathways that control the differentiation and function of osteoclasts and bone mineral homeostasis.

Biography

Dr. Yang received his M.D. degree from Lanzhou University School of Medicine and Ph.D. degree in Molecular Biology from Sichuan University School of Medicine in China. He completed his post-doctoral training in the field of cellular signal transduction with Dr. Benjamin G. Neel at Harvard Medical School. Currently, Dr. Yang is appointed as an assistant professor of Orthopaedics and Medicine at the department of Orthopaedics of Brown Alpert Medical School.

Research Description

Musculoskeletal disorders and diseases that cause cartilage degeneration or bone mineral loss remain the leading cause of disability, significantly affecting the quality of life. At the cellular level, three types of cells are primarily responsible for building and maintaining healthy bone and cartilage, which are osteoblasts (OB), chondrocytes and osteoclasts (OC). Understanding the molecular and cellular mechanisms by which the development and homeostasis of OB, chondrocytes and OC are regulated will lay a new foundation on which novel therapeutics could be developed to prevent and/or treat skeletal disorders.
It is well known that protein tyrosine kinase (PTK) signaling is critical in regulation of chondrogenesis. In contrast, little is known about the role of protein tyrosine phosphatases (PTP) in this context. SHP2, encoded by the PTPN11 gene, is one of two vertebrate Src homology-2 domain containing PTP. SHP2 is ubiquitously expressed and its loss-of-function mutations were recently linked to human cartilage tumor syndrome metachondromatosis, implicating an important role for SHP2 in cartilage development and homeostasis. In a recent study aimed at characterizing the skeletal phenotype of mice lacking Shp2 in chondroid cells at various developmental stages, we identified a novel population of Ctsk-expressing chondroid progenitors (CCP) in joints; Shp2 was shown to negatively regulate the proliferation and chondrocytic terminal differentiation of CCP and osteochondroprogenitors. Currently we are investigating the molecular and cellular mechanisms by which SHP2 modulates chondrogenesis and cartilage homeostasis.
Osteoclasts (OC) are the exclusive bone resorbing cells in mammals, playing a central role in the formation of skeleton and regulation of bone mass. Dysregulation of the development and function of OC is linked to several skeletal diseases, such as osteoporosis, osteopetrosis and periprosthetic osteolysis, significantly affecting the quality of life. OC originate from hematopoietic cells, their differentiation along OC lineage requires the cellular signaling initiated by two key growth factors: macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL). Another direction of our research is to understand how osteoclastogenesis is regulated by M-CSF and RANKL-evoked signaling cascades. By using genetic loss-of-function approaches and other biochemical means, we recently identified Shp2 as a key regulator downstream RANK to promote the expression of nuclear factor of activated T cells (NFATc1) and the fusion of preosteoclasts; inhibition of this signaling pathway can compromise mature osteoclast formation and reduce bone mineral loss. We are fascinated by these findings and expect that the outcome of these studies would add a new dimension regarding the prevention and treatment of periprosthetic osteolysis and osteoporosis.

Affiliations

American Society of Hematology since 1996
Orthopaedic Research Society since 2007
American Society of Bone and Mineral Research 2009
International Society of Microvesicle Research 2010
International Chinese Hard Tissue Association 2007

Funded Research

NIH COBRE for Stem Cell biology 1P20 RR025179 7/09-7/14
Project III (PI: Yang): Shp2 in Hematopoietic Stem Cell Property Maintenance
The major goal of this project is to understand how Shp2 regulates hematopoietic and cartilage stem cell self-renewal and multilineage differentiation.

NIH R21AR057156 Yang (PI) 10/09-9/12
"Shp2 in Osteoclastogenesis and Bone Remodeling"
The major goal of this project is to understand the biological and biochemical role of Shp2 in osteoclast development and function

Pediatric Orthopaedic Society of North America Research Grant Yang (PI) 6/08-5/09
"Shp2 Regulation of c-Fms Signaling and Myeloid Monocytic Cell Development"

Teaching Experience

Primary graduate program affiliation:
BioMed/Pathobiology

Primary undergraduate program affiliation:
BioMed/biology

Selected Publications

  • Kairong Li, Alan Leung, Qiuxia Guo, Wentian Yang, and James Li Shp2-dependent ERK signaling is essential for induction of Bergmann glia and foliation of the cerebellum. Journal of Neuroscience 2014. 34(3):922-931. DOI:doi:10.1523/JNEUROSCI.3476-13.PMID: 24431450 (2014)
  • Sun X, Charbonneau C, Wei L, Yang W, Chen Q, Terek RM. CXCR4-Targeted Therapy Inhibits VEGF Expression and Chondrosarcoma Angiogenesis and Metastasis. Mol Cancer Ther. 2013 Jun 27. PMID: 23686836. (2013)
  • Yang W & Neel BG. From an orphan disease to a generalized molecular mechanism: PTPN11 loss-of-function mutations in the pathogenesis of metachondromatosis. Rare Diseases 2013; 1:e26657. (2013)
  • Yang W, Wang J, Moore DC, Liang H, Dooner M, Wu Q, Terek RM, Chen Q, Ehrlich MG, Quesenberry PJ, Neel BG. Ptpn11 deletion in a novel progenitor causes metachondromatosis by inducing hedgehog signaling. Nature, 499(7459):491-5, 2013. [Editorial comments by Nature: Cell biology: tumour stem cells in bone. Nature. 2013 Jul 25;499(7459):414-6] PMID:23863940. (2013)
  • Gordon Chan, Wentian Yang, Laurene S. Cheung, Michael Milyavsky, Ashley D. Sanders, Shengqing Gu, Wan Xing Hong, Aurora X. Liu, Xiaonan Wang, Mary Barbara4, Tarun Sharma, Joehleen Gavin, Jeffery L. Kutok, Norman N. Iscove4, Kevin M. Shannon, John E. Dick, Benjamin G. Neel1, and Benjamin S. Braun Essential role for Ptpn11 (Shp2) in survival of hematopoietic stem and progenitor cells. Blood. 2011 Apr 21;117(16):4253-61. PMID:21398220. (2011)
  • Wentian Yang A new model for remodeling. Journal of International Innovation 2011. 4:42-44. (2011)
  • Ryoichi Banno, Derek Zimmer, Marybless Atienza, Kimberly Rak, Wentian Yang, and Kendra K. Bence. PTP1B- or SHP2-deficiency in POMC neurons reciprocally regulates energy balance, glucose homeostasis, and hepatic steatosis. Journal of Clinical Investigation. 2010 Mar 1;120(3):720-34. PMID: 20160350 (2010)
  • Matsuo K, Delibegovic M, Matsuo I, Nagata N, Liu S, Bettaieb A, Xi Y, Araki K, Yang W, Kahn BB, Neel BG, Haj FG. Altered glucose homeostasis in mice with liver-specific deletion of Src homology phosphatase 2. J Biol Chem. 2010;285(51):39750-8. PMID:20841350 (2010)
  • Maria I. Kontaridis, Wentian Yang, Kendra K. Bence, Darragh Cullen, Bo Wang, Natalya Bodyak, Qingen Ke, Aleksander Hinek, Peter M. Kang, Ronglih Liao, and Benjamin G. Neel. Deletion of Ptpn11 (Shp2) in cardiomyocytes leads to dilated cardiomyopathy. Circulation 2008 Mar 18;117(11):1423-35. PMID: 18316486 (2008)
  • Kyung-Hyun Park-Min, Natalya V. Serbina, Wentian Yang, Xiaojing Ma, Stephen L. Nutt, Xiaoyu Hu, Benjamin G. Neel and Lionel B. Ivashkiv. FcγRIII-dependent Inhibition of IFN-γ Responses Mediates Suppressive Effects of IVIG. Immunity 2007. 26(1): 67-78. PMID: 17239631 (2007)
  • Wentian Yang, Lori D. Klaman, Binbin Chen, Toshiyuki Araki, Hisashi Harada, Sheila M. Thomas, Elizabeth L.George, Benjamin G. Neel. An Shp2/SFK/Ras/Erk Signaling Pathway Controls Trophoblast Stem Cell Survival. Developmental Cell, 2006. 10(3): 317-327. [Editorial comments by Developmental Cell 2006;10(3):275-6. How signaling promotes stem cell survival: trophoblast stem cells and Shp2]. PMID:16516835. (2006)
  • Zhimei Du, Yuhong Shen, Ingrid Mecklenbrauker, Wentian Yang, Benjamin G. Neel and Lionel B. Ivashkiv. Inhibition of IFNα signaling by a PKC and SHP2 dependent pathway. PNAS 2005. 102(29):10267-10272. PMID:16000408 (2005)
  • Rusanescu Gabriel, Wentian Yang, Ailin Bai, Benjamin G. Neel and Larry A Feig Tyrosine phosphatase SHP2 is a mediator of activity-dependent neuronal excitotoxicity EMBO J. 2005 Jan 26;24(2):305-14. PMID: 15650750 (2005)
  • Toshiyuki Araki, M Golam Mohi, Fraz A Ismat, Roderick T Bronson, Ifor R Williams, Jeffery L Kutok, Wentian Yang, Lily I Pao, D Gary Gilliland, Jonathan A Epstein & Benjamin G Neel. Mouse model of Noonan syndrome reveals cell type- and gene dosage –dependent effects of Ptpn11 mutation. Nature Medicine 2004. 10(8):849-857. PMID: 15273746 (2004)
  • Wentian Yang (Co-first authorship), Siqing Zhang, Maria I. Kontaridis1, Trever G. Bivona, , Gengyun Wen, Toshiyuki Araki, Jincai Luo, Julie A. Thompson, Burkhart L. Schraven, Mark R. Philips, and Benjamin G. Neel. Shp2 regulates SRC family kinase activity and ras/erk activation by controlling csk recruitment. Molecular Cell 2004. 13(3):341. PMID: 14967142. (2004)