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Fertala J¹, Arita M¹, Steplewski A¹, Arnold WV^1,2, Fertala A¹

¹Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA; ²Rothman Institute of Orthopaedics, Thomas Jefferson University Hospital, Philadelphia, PA, USA

Bone 2018;112:42–50

Spondyloepiphyseal dysplasia (SED) exemplifies a group of heritable diseases caused by mutations in collagenous proteins of the skeletal system. Its main feature is altered skeletal growth. Pathomechanisms of SED include: changes in the stability of collagen II molecules, inability to form proper collagen fibrils, excessive intracellular retention of mutant molecules, and endoplasmic reticulum stress. The complexity of this pathomechanism presents a challenge for designing therapies for SED.

Our earlier research tested whether such therapies only succeed when applied during a limited window of development. Here, employing an inducible mouse model of SED caused by the R992C mutation in collagen II, we corroborate our earlier observations that a therapy must be applied at the prenatal or early postnatal stages of skeletal growth in order to be successful. Moreover, we demonstrate that blocking the expression of the R992C collagen II mutant at the early prenatal stages leads to long-term positive effects. Although, we could not precisely mark the start of the expression of the mutant, these effects are not significantly changed by switching on the mutant production at the early postnatal stages.

By demonstrating the need for early therapeutic interventions, our study provides, for the first time, empirically-based directions for designing effective therapies for SED and, quite likely, for other skeletal dysplasias caused by mutations in key macromolecules of the skeletal system.

Reprinted with permission from Elsevier.

Comments

Studying mechanisms involved in rare bone dysplasias not only is important from the perspective of a specific bone disease but also may be applied for diagnostic and therapeutic procedure in other diseases of altered skeletal growth [11]. In the present study, timing of therapy during an individual’s development was studied. In an animal model, it was determined as successful in the long term only if it is applied at the prenatal or early postnatal stages of skeletal growth [12]. Confirming an early initiation of treatment might be of importance also in other disorders of skeletal growth, affecting not only planning of timing and modes of treatment administration but also very early diagnosis.

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