title: Reducing the effects of intracellular accumulation of thermolabile collagen II mutants by increasing their thermostability in cell culture conditions.
abstract: Mutations in collagen II are associated with spondyloepiphyseal dysplasia, a group of heritable diseases whose common features include aberrations of skeletal growth. The mechanisms through which mutations in collagen II affect the cartilaginous tissues are complex and include both intracellular and extracellular processes. One of those mechanisms involves cellular stress caused by excessive accumulation of misfolded collagen II mutants. We investigated whether stabilizing the structure of thermolabile R789C and R992C collagen II mutants would improve their secretion from cells, thereby reducing cellular stress and apoptosis. Employing glycerol and trimethylamine N-oxide (TMAO), chemicals that increase the thermostability of collagen triple helices, we demonstrated that those compounds function as chaperones and stabilize the R789C and R992C mutants, accelerate their secretion, and improve cell survival. Our study provides a scientific basis for considering misfolded triple helices of collagen mutants a target for reducing the deleterious effects caused by their excessive intracellular accumulation.
authors.affiliation: Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Gawron
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Jensen
authors.forename: Andrzej
authors.initials: A
authors.lastname: Steplewski
authors.forename: Andrzej
authors.initials: A
authors.lastname: Fertala
mesh_terms: D017209:Apoptosis; D018929:Cell Culture Techniques; D024043:Collagen Type II / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005990:Glycerol / Q000737:chemistry / Q000494:pharmacology; D006358:Hot Temperature; D006801:Humans; D008744:Methylamines / Q000737:chemistry / Q000494:pharmacology; D009154:Mutation; D010009:Osteochondrodysplasias / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D055550:Protein Stability
chemical_list: D024043:Collagen Type II; D008744:Methylamines; C005855:trimethyloxamine; D005990:Glycerol
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