Limb- and tendon-specific Adamtsl2 deletion identifies a soft tissue mechanism modulating bone length

Abstract

AbstractDisproportionate distal limb shortening is the hallmark of acromelic dysplasias. Among them, geleophysic dysplasia is a rare, frequently lethal condition characterized by severe short stature, musculoskeletal, cardiac, pulmonary, and skin anomalies. Geleophysic dysplasia results from dominant fibrillin-1 (FBN1) or recessive ADAMTSL2 mutations, suggesting a functional link between ADAMTSL2 and FBN1. Mice lacking ADAMTSL2 die at birth, precluding analysis of postnatal skeletal growth and mechanisms underlying the skeletal anomalies of geleophysic dysplasia. We show that Adamtsl2 is expressed in limb soft tissues, predominantly in tendon. Expression in developing bones is limited to their terminal cell layers that are destined to become articular cartilage and is absent in growth plate cartilage. Adamtsl2 conditional deletion in limb mesenchyme using Prxl-Cre led to an acromelic dysplasia, providing a suitable model for investigation of geleophysic dysplasia. Unexpectedly, conditional Adamtsl2 deletion using Scx-Cre, a tendon-specific deleter, also impaired skeletal growth. Specific morphogenetic anomalies were seen in Achilles tendon, along with FBN1 accumulation. Thus, ADAMTSL2, shown here to bind fibrillin microfibrils in vitro, limits fibrillin microfibril formation in tendons and promotes tendon growth. The findings suggest that reduced bone growth in geleophysic dysplasia results from external tethering by short tendons rather than intrinsic growth plate anomalies.