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Abstract
Studies have shown that mutations in the matrilin-3 gene (MATN3) are associated with multiple epiphyseal dysplasia (MED) and spondyloepimetaphyseal dysplasia (SEMD). We tested whether MATN3 mutations affect the differentiation of chondroprogenitor and/or mesenchymal stem cells, which are precursors to chondrocytes. ATDC5 chondroprogenitors stably expressing wild-type (WT) MATN3 underwent spontaneous chondrogenesis. Expression of chondrogenic markers collagen II and aggrecan was inhibited in chondroprogenitors carrying the MED or SEMD MATN3 mutations. Hypertrophic marker collagen X remained attenuated in WT MATN3 chondroprogenitors, whereas its expression was elevated in chondroprogenitors expressing the MED or SEMD mutant MATN3 gene suggesting that these mutations inhibit chondrogenesis but promote hypertrophy. TGF-β treatment failed to rescue chondrogenesis markers but dramatically increased collagen X mRNA expression in mutant MATN3 expressing chondroprogenitors. Synovium derived mesenchymal stem cells harboring the SEMD mutation exhibited lower glycosaminoglycan content than those of WT MATN3 in response to TGF-β. Our results suggest that the properties of progenitor cells harboring MATN3 chondrodysplasia mutations were altered, as evidenced by attenuated chondrogenesis and premature hypertrophy. TGF-β treatment failed to completely rescue chondrogenesis but instead induced hypertrophy in mutant MATN3 chondroprogenitors. Our data suggest that chondroprogenitor cells should be considered as a potential target of chondrodysplasia therapy.
Highlights
Endochondral bone formation is the primary means of skeletal development in vertebrates
Several cell lines were established by stably transfecting ATDC5 cells with WT, multiple epiphyseal dysplasia (MED) or spondyloepimetaphyseal dysplasia (SEMD) matrilin-3 gene (MATN3) gene constructs
The full length WT MATN3 protein that was secreted into the cell media formed primarily tetramers along with trimer, dimer and monomer (Figure 2), which is similar to the results previously described in chondrocytes [16,20]
Summary
Endochondral bone formation is the primary means of skeletal development in vertebrates. During this process, growth plate chondrocytes undergo rapid proliferation and differentiation into mature chondrocytes. Growth plate chondrocytes undergo rapid proliferation and differentiation into mature chondrocytes These chondrocytes further differentiated into hypertrophic chondrocytes that, in time, ossify as the diaphysis elongates resulting in long bone growth. The crippling effects of chondrodysplasia illustrate the importance of cartilage development to the process of normal bone growth. MATN3 is a small non-collagenous extracellular matrix (ECM) protein consisting of a von Willebrand factor A (vWFA) domain, four consecutive epidermal growth factor (EGF) repeats and a single coiled-coil domain [3]. Despite our current understanding of its molecular interaction with other cartilage ECM proteins, such as type II/IX collagens [5,6], cartilage oligomeric matrix protein COMP [7] and matrilin-1 (MATN1) [3,8,9,10], the biological role of MATN3 remains largely unknown
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