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

Abstract

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.

A novel role in skeletal segment regeneration of extracellular vesicles released from periodontal-ligament stem cells

“…According to these results, in the presence of PEI-EVs, qRT-PCR showed upregulation of key genes involved in the bone-differentiation pathway, such as TUFT1, TFIP11, BMP2-BMP4, and TGFB. TUFT1 expression in cartilage has demonstrated to be strongest in the deep, mineralizing zones, 51 and its expression has been shown to be regulated in vitro by HIF1α and Hedgehog pathways, both essential elements involved in cartilage and bone formation. 52 TFIP11 is a gene involved in pre-mRNA splicing, specifically in spliceosome disassembly during late-stage splicing events that may play a role in the differentiation of ameloblasts and odontoblasts or in the formation of the extracellular mineralized matrix.…”

Effects of oral glucosamine hydrochloride and mucopolysaccharide protein in a rabbit model of osteoarthritis

“…Osteoarthritis (OA), the most common degenerative joint disease, is characterized by progressive loss of cartilage, periarticular bone changes and chronic synovitis that lead to joint swelling and pain . OA most often affects the knees, hips, neck, finger joints and lower back .…”

Familial clustering of erosive hand osteoarthritis in a large statewide cohort

“…The study of rare variants in affected families is a powerful way to identify gene variants with a determinate effect on disease development. [47][48][49][50] Using the UPDB, we have identified 240 large multigenerational, high-risk pedigrees segregating EOA as an apparent dominate trait. Although a previous study described association of EOA in sibling pairs 24 , our study is the first to identify a large number of multigenerational EOA pedigrees and determine relative risk among family members.…”