Collagen misfolding mutations: the contribution of the unfolded protein response to the molecular pathology

The effect of carbamazepine on bone structure and strength in control and osteogenesis imperfecta (Col1a2+/p.G610C) mice

“…The cellular response to the disturbed proteostasis resulting from collagen I misfolding, and whether a canonical or 'non-canonical' UPR results remains unclear with many mutations, especially those disturbing the triple helix. 8 Those impacting the C-propeptide may be more likely to elicit a canonical UPR 8 and it is tempting to speculate that CBZ may be more effective with these given their similarity to the CBZ-responsive collagen X mutations, 11 and the positive effect of 4-PBA on the Aga2 +/− mice. 25 While CBZ treatment could show mutation specificity in its effect, the use of CBZ as a OI therapeutic is, however, moot since we found that the 6-week CBZ treatment of 3-week-old growing bone in control mice was deleterious.…”

“…Thus, 4‐PBA may be effective for some OI mutations, less so for others, most likely due to the nature of the collagen folding defects caused by different mutations and the resulting cellular response to the misfolded collagen. The cellular response to the disturbed proteostasis resulting from collagen I misfolding, and whether a canonical or ‘non‐canonical’ UPR results remains unclear with many mutations, especially those disturbing the triple helix 8 . Those impacting the C‐propeptide may be more likely to elicit a canonical UPR 8 and it is tempting to speculate that CBZ may be more effective with these given their similarity to the CBZ‐responsive collagen X mutations, 11 and the positive effect of 4‐PBA on the Aga 2 +/− mice 25 …”

“…While the molecular detail of how helix‐disrupting OI mutations cause intracellular ER stress and bone pathology are not fully resolved, 8 a promising therapeutic approach would be to reduce the load of toxic misfolded collagen and thereby reduce the OI bone pathology to a milder phenotype. There are few FDA‐approved drugs that could be re‐purposed to achieve this.…”

“…Previous studies on this mouse model have shown that, as expected, the glycine substitution mutation leads to intracellular mutant collagen accumulation, a poorly characterized non-canonical ER stress response and downstream impairment in osteoblast differentiation and function 6 with clinically relevant changes to bone structure and fragility. 7 While the molecular detail of how helix-disrupting OI mutations cause intracellular ER stress and bone pathology are not fully resolved, 8 a promising therapeutic approach would be to reduce the load of toxic misfolded collagen and thereby reduce the OI bone pathology to a milder phenotype. There are few FDA-approved drugs that could be re-purposed to achieve this.…”

Molecular Basis of Pathogenic Variants in the Fibrillar Collagens

“…Structural abnormalities to the Gly-X-Y repeat may also result in misalignment of the N-proteinase cleavage site [ 26 , 27 ], resulting in inefficient removal or failure to remove the N-propeptide (see Section 3.7 ). It has also been found that not only is there reduced secretion and structurally abnormal collagen, but the intracellularly retained molecules can have an adverse effect on cell viability (reviewed in [ 28 ]).…”