Cartilage diseases remain among the most costly musculoskeletal disorders, their treatment continues to be a major clinical challenge. Lack of adequate knowledge regarding the molecular and cellular mechanisms that regulate chondrogenesis primarily causes this scenario. The goal of this proposal attempts to fill this knowledge gap by studying how the development and homeostasis of cartilage are regulated by the newly identified population of cathepsin K (Ctsk)-expressing chondroid progenitors (CCP) and by the cytoplasmic protein tyrosine phosphatase SHP2 (encoded by PTPN11). In a recent study aimed at characterizing the skeletal phenotype of mice lacking SHP2 in Ctsk- expressing cells, we made two important and interrelated discoveries (Nature, 2013. 499:491-5). First, we identified a novel population of CCP which primarily reside in the perichondrial groove of Ranvier and also sparsely scatter in articular and growth plate cartilage. CCP express mesenchymal stem cell (MSC) surface markers and appear to play a role in cartilage development and homeostasis. Second, we found that SHP2 functions as a tumor suppressor in cartilage: SHP2 deletion in CCP in mice yields a striking skeletal phenotype, featuring the growth of osteochondromas and enchondromas in bone. These skeletal diseases recapitulate the clinical features of metachondromatosis, a cartilage tumor syndrome in humans in which heterozygous SHP2 loss-of-function (LOF) mutations have been identified. Our findings strongly suggest that CCP are a phenotypically and functionally distinct pool of cartilage stem cells, and SHP2 is a key modulator of CCP and possibly other chondroid cells during chondrogenesis. Little is known about the regulatory role of SHP2 in chondrogenesis and cartilage homeostasis, in contrast to the vast literature regarding protein tyrosine kinase signaling in this context. We hypothesize that CCP are cartilage stem cells; SHP2 regulates fate decisions of CCP and chondrogenesis by influencing the expression and transcriptional activity of the master chondrogenic transcription factor SOX9. Altered SOX9 expression and transcriptional activity as a result of SHP2 deficiency can cause excessive cell proliferation, differentiation and cartilaginous neoplasm. The specific objectives of this proposal are to determine CCP, to what extent, are truly cartilage stem cells; and mechanistically how SHP2 regulates chondrogenesis and SHP2 loss-of-heterozygosity mutations cause cartilage tumorigenesis. Our long-term objective is to develop strategies to inhibit cartilage degeneration and promote its regeneration and homeostasis by mobilizing CCP and/or modifying SHP2-regulated signaling pathway(s). The outcome of this study will shed new light on the development of novel therapeutics and regenerative approaches to a spectrum of cartilage diseases, from tumors to osteoarthritis.

Public Health Relevance

We propose to study the biology of the newly identified cathepsin K-expressing chondroid progenitors (CCP) and to define the molecular mechanism through which SHP2 regulates chondrogenesis and cartilage tumorigenesis. Completion of the aims proposed will advance our knowledge regarding the role of CCP in cartilage development and anti-degeneration, the initiation and progression of cartilage tumors, and the regulatory role of PTPN11 in cartilage. The outcome of this study will shed new light on the development of novel therapeutics and regenerative approaches to a spectrum of cartilage diseases, from tumors to osteoarthritis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR066746-05
Application #
9766824
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Kirilusha, Anthony G
Project Start
2015-09-21
Project End
2020-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Rhode Island Hospital
Department
Type
DUNS #
075710996
City
Providence
State
RI
Country
United States
Zip Code
02903
Wang, Lijun; Iorio, Caterina; Yan, Kevin et al. (2018) A ERK/RSK-mediated negative feedback loop regulates M-CSF-evoked PI3K/AKT activation in macrophages. FASEB J 32:875-887
Gu, S; Sayad, A; Chan, G et al. (2018) SHP2 is required for BCR-ABL1-induced hematologic neoplasia. Leukemia 32:203-213
Zuo, Chunlin; Wang, Lijun; Kamalesh, Raghavendra M et al. (2018) SHP2 regulates skeletal cell fate by modifying SOX9 expression and transcriptional activity. Bone Res 6:12
Wang, Lijun; Huang, Jiahui; Moore, Douglas C et al. (2018) SHP2 regulates intramembranous ossification by modifying the TGF? and BMP2 signaling pathway. Bone 120:327-335
Miah, S M Shahjahan; Jayasuriya, Chathuraka T; Salter, Alexander I et al. (2017) Ptpn11 Deletion in CD4+ Cells Does Not Affect T Cell Development and Functions but Causes Cartilage Tumors in a T Cell-Independent Manner. Front Immunol 8:1326
Wang, Lijun; Huang, Jiahui; Moore, Douglas C et al. (2017) SHP2 Regulates the Osteogenic Fate of Growth Plate Hypertrophic Chondrocytes. Sci Rep 7:12699
Vesprey, Alexander; Yang, Wentian (2016) Pit Assay to Measure the Bone Resorptive Activity of Bone Marrow-derived Osteoclasts. Bio Protoc 6:
Liu, Xia; Zheng, Hong; Li, Xiaobo et al. (2016) Gain-of-function mutations of Ptpn11 (Shp2) cause aberrant mitosis and increase susceptibility to DNA damage-induced malignancies. Proc Natl Acad Sci U S A 113:984-9