University of Oulu

Sliz E, Taipale M, Welling M, Skarp S, Alaraudanjoki V, Ignatius J, et al. (2017) TUFT1, a novel candidate gene for metatarsophalangeal osteoarthritis, plays a role in chondrogenesis on a calcium-related pathway. PLoS ONE 12(4): e0175474.

TUFT1, a novel candidate gene for metatarsophalangeal osteoarthritis, plays a role in chondrogenesis on a calcium-related pathway

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Author: Sliz, Eeva1,2,3; Taipale, Mari1,2,3; Welling, Maiju1,2,4;
Organizations: 1Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
2Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
3Biocenter Oulu, University of Oulu, Oulu, Finland
4Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
5Research Unit of Oral Health Sciences, University of Oulu, University of Oulu, Oulu, Finland
6Department of Clinical Genetics, Turku University Hospital, Turku, Finland
7Department of Obstetrics and Gynecology, Oulu University Hospital, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.8 MB)
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Language: English
Published: Public Library of Science, 2017
Publish Date: 2017-06-28


Osteoarthritis (OA) is the most common degenerative joint disorder and genetic factors have been shown to have a significant role in its etiology. The first metatarsophalangeal joint (MTP I) is highly susceptible to development of OA due to repetitive mechanical stress during walking. We used whole exome sequencing to study genetic defect(s) predisposing to familial early-onset bilateral MTP I OA inherited in an autosomal dominant manner. A nonsynonymous single nucleotide variant rs41310883 (c.524C>T, p.Thr175Met) in TUFT1 gene was found to co-segregate perfectly with MTP I OA. The role of TUFT1 and the relevance of the identified variant in pathogenesis of MTP I OA were further assessed using functional in vitro analyses. The variant reduced TUFT1 mRNA and tuftelin protein expression in HEK293 cells. ATDC5 cells overexpressing wild type (wt) or mutant TUFT1 were cultured in calcifying conditions and chondrogenic differentiation was found to be inhibited in both cell populations, as indicated by decreased marker gene expression when compared with the empty vector control cells. Also, the formation of cartilage nodules was diminished in both TUFT1 overexpressing ATDC5 cell populations. At the end of the culturing period the calcium content of the extracellular matrix was significantly increased in cells overexpressing mutant TUFT1 compared to cells overexpressing wt TUFT1 and control cells, while the proteoglycan content was reduced. These data imply that overexpression of TUFT1 in ATDC5 inhibits chondrogenic differentiation, and the identified variant may contribute to the pathogenesis of OA by increasing calcification and reducing amount of proteoglycans in the articular cartilage extracellular matrix thus making cartilage susceptible for degeneration and osteophyte formation.

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Series: PLoS one
ISSN: 1932-6203
ISSN-E: 1932-6203
ISSN-L: 1932-6203
Volume: 12
Issue: 4
Article number: e0175474
DOI: 10.1371/journal. pone.0175474
OADOI: pone.0175474
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: This study was funded by the University of Oulu (university researcher recruitment funding, MM)
Dataset Reference: The exome data were deposited to NIH SRA with submission ID PRJNA373947, and are available from
Copyright information: Copyright: © 2017 Sliz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.