Increased intracellular proteolysis reduces disease severity in an ER stress-associated dwarfism

• Published in: The Journal of clinical investigation Vol. 127; no. 10; pp. 3861 - 3865
• Main Authors: Mullan, Lorna A, Mularczyk, Ewa J, Kung, Louise H, Forouhan, Mitra, Wragg, Jordan Ma, Goodacre, Royston, Bateman, John F, Swanton, Eileithyia, Briggs, Michael D, Boot-Handford, Raymond P
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.10.2017
• Subjects: Activating Transcription Factor 4 - genetics; Activating Transcription Factor 4 - metabolism; Animals; Autophagy; Biomedical research; Bipolar disorder; Bone dysplasia; Bone growth; Brief Report; Carbamazepine; Carbamazepine - pharmacology; Cartilage cells; Cell culture; Chondrocytes; Chondrocytes - metabolism; Chondrocytes - pathology; Chondrodystrophy; Chondrogenesis; Collagen; Collagen (type X); Collagen Type X - biosynthesis; Collagen Type X - genetics; Drug dosages; Dwarfism; Dwarfism - genetics; Dwarfism - metabolism; Dwarfism - pathology; Endoplasmic reticulum; Endoplasmic Reticulum Stress; Gene mutation; Glycerol; Growth plate; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; Hospital emergency services; Humans; Intracellular; Mice; Mutation; Phagocytosis; Proteasomes; Protein folding; Proteins; Proteolysis; Rodents; Seizures; Skeleton
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci93094

The short-limbed dwarfism metaphyseal chondrodysplasia type Schmid (MCDS) is linked to mutations in type X collagen, which increase ER stress by inducing misfolding of the mutant protein and subsequently disrupting hypertrophic chondrocyte differentiation. Here, we show that carbamazepine (CBZ), an autophagy-stimulating drug that is clinically approved for the treatment of seizures and bipolar disease, reduced the ER stress induced by 4 different MCDS-causing mutant forms of collagen X in human cell culture. Depending on the nature of the mutation, CBZ application stimulated proteolysis of misfolded collagen X by either autophagy or proteasomal degradation, thereby reducing intracellular accumulation of mutant collagen. In MCDS mice expressing the Col10a1.pN617K mutation, CBZ reduced the MCDS-associated expansion of the growth plate hypertrophic zone, attenuated enhanced expression of ER stress markers such as Bip and Atf4, increased bone growth, and reduced skeletal dysplasia. CBZ produced these beneficial effects by reducing the MCDS-associated abnormalities in hypertrophic chondrocyte differentiation. Stimulation of intracellular proteolysis using CBZ treatment may therefore be a clinically viable way of treating the ER stress-associated dwarfism MCDS.