Abstract
Skeletal dysplasias form a group of skeletal disorders caused by mutations in macromolecules of cartilage and bone. The severity of skeletal dysplasias ranges from precocious arthropathy to perinatal lethality. Although the pathomechanisms of these disorders are generally well defined, the feasibility of repairing established aberrant skeletal tissues that developed in the presence of mutant molecules is currently unknown. Here, we employed a validated mouse model of spondyloepiphyseal dysplasia (SED) that enables temporal control of the production of the R992C (p.R1192C) collagen II mutant that causes this disease. Although in our earlier studies we determined that blocking the expression of this mutant at the early prenatal stages prevents a SED phenotype, the utility of blocking the R992C collagen II at the postnatal stages is not known. Here, by switching off the expression of R992C collagen II at various postnatal stages of skeletal development, we determined that significant improvements of cartilage and bone morphology were achieved only when blocking the production of the mutant molecules was initiated in newborn mice. Our study indicates that future therapies of skeletal dysplasias may require defining a specific time window when interventions should be applied to be successful.
Highlights
During prenatal development, various collagen types contribute to shaping the embryonic cartilaginous skeleton and maintaining its structural integrity
We did not directly measure the time from starting the Dox treatment to blocking the expression of the ProGFP in the DoxR992C-ProGFP(+) mice, our earlier studies on chondrocytes isolated from the R992C-ProGFP(+) mice indicated that the expression stops after 48 h [25]
In our earlier studies on the mild form of spondyloepiphyseal dysplasia (SED) caused by the R992C collagen II, we demonstrated perturbations of the growth plates in mice harboring this mutant [25]
Summary
Various collagen types contribute to shaping the embryonic cartilaginous skeleton and maintaining its structural integrity. This defines the spatial organization of chondrocytes whose biological activities control bone growth. In a postnatal growth plate, chondrocytes arrange into columns within which specific cell subpopulations form the resting, proliferating, pre-hypertrophic, and hypertrophic zones. These chondrocytes interact, via receptors, with the extracellular matrix (ECM) of the growth plate to maintain this. Documented aberrations of skeletal growth due to mutations in COL2A1 confirm the key role of collagen II in bone development [3]. Mutations in collagen II may increase intracellular accumulation of mutant chains and molecules that interact with them, e.g. fibronectin, causing endoplasmic reticulum (ER) stress [3, 5]
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