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Abstract
Aggrecan is an integral component of the extracellular matrix in cartilaginous tissues, including the growth plate. Heterozygous defects in the aggrecan gene have been identified as a cause of autosomal dominant short stature, bone age acceleration, and premature growth cessation. The mechanisms accounting for this phenotype remain unknown. We used ATDC5 cells, an established model of chondrogenesis, to evaluate the effects of aggrecan deficiency. ATDC5 aggrecan knockdown cell lines (AggKD) were generated using lentiviral shRNA transduction particles. Cells were stimulated with insulin/transferrin/selenium for up to 21 days to induce chondrogenesis. Control ATDC5 cells showed induction of Col2a1 starting at day 8 and induction of Col10a1 starting at day 12. AggKD cells had significantly reduced expression of Col2a1 and Col10a1 (p<0.0001) with only minimal increases in expression over time, indicating that chondrogenesis was markedly impaired. The induction of Col2a1 and Col10a1 was not rescued by culturing of AggKD cells in wells pre-conditioned with ATDC5 extracellular matrix or in co-culture with wild-type ATDC5 cells. We interpret our studies as indicating that aggrecan has an integral role in chondrogenesis that may be mediated through intracellular mechanisms.
Highlights
Aggrecan is a core protein with chondroitin and keratan sulfate side chains that is an integral part of the extracellular matrix in cartilaginous tissue [1]
Heterozygous defects in the aggrecan gene have been identified as a cause of autosomal dominant short stature, bone age acceleration, and premature growth cessation, all of which are consistent with a role for aggrecan in the cartilaginous growth plate
ATDC5 cells were transduced with lentiviral transduction particles to create aggrecan knockdown cell lines (AggKD) cell lines and control cell lines
Summary
Aggrecan is a core protein with chondroitin and keratan sulfate side chains that is an integral part of the extracellular matrix in cartilaginous tissue [1]. Heterozygous defects in the aggrecan gene have been identified as a cause of autosomal dominant short stature, bone age acceleration, and premature growth cessation, all of which are consistent with a role for aggrecan in the cartilaginous growth plate. Of the 20 families far identified with so-called “aggrecanopathies” [2,3], 12 of the families have early onset osteoarthritis, and 11 have degenerative intervertebral disc disease [3,4,5]. Of particular significance to the phenotype in these families is bone age acceleration, an atypical finding in short stature of other etiologies.
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