Altered versican cleavage in ADAMTS5 deficient mice; A novel etiology of myxomatous valve disease

Abstract

In fetal valve maturation the mechanisms by which the relatively homogeneous proteoglycan-rich extracellular matrix (ECM) of endocardial cushions is replaced by a specialized and stratified ECM found in mature valves are not understood. Therefore, we reasoned that uncovering proteases critical for ‘remodeling’ the proteoglycan rich (extracellular matrix) ECM may elucidate novel mechanisms of valve development. We have determined that mice deficient in ADAMTS5, (A Disintegrin-like And Metalloprotease domain with ThromboSpondin-type 1 motifs) which we demonstrated is expressed predominantly by valvular endocardium during cardiac valve maturation, exhibited enlarged valves. ADAMTS5 deficient valves contained a reduction in cleavage of its substrate versican, a critical cardiac proteoglycan. In vivo reduction of versican, in Adamts5−/− mice, achieved through Vcan heterozygosity, substantially rescued the valve anomalies. An increase in BMP2 immunolocalization, Sox9 expression and mesenchymal cell proliferation were observed in Adamts5−/− valve mesenchyme and correlated with expansion of the spongiosa (proteoglycan-rich) region in Adamts5−/− valve cusps. Furthermore, these data suggest that ECM remodeling via ADAMTS5 is required for endocardium to mesenchymal signaling in late fetal valve development. Although adult Adamts5−/− mice are viable they do not recover from developmental valve anomalies and have myxomatous cardiac valves with 100% penetrance. Since the accumulation of proteoglycans is a hallmark of myxomatous valve disease, based on these data we hypothesize that a lack of versican cleavage during fetal valve development may be a potential etiology of adult myxomatous valve disease.

Versican Processing by a Disintegrin-like and Metalloproteinase Domain with Thrombospondin-1 Repeats Proteinases-5 and -15 Facilitates Myoblast Fusion

“…The proteolysis of versican by ADAMTS proteinases is implicated in morphogenesis of the myocardium, heart valves, secondary palate, urogenital system (43)(44)(45), and interdigital web regression (20) during mouse embryogenesis, as well as ovulation in female mice (28,46). ADAMTS proteinases act alone or cooperatively in some of these contexts, such as web regression and palate closure.…”

Transcriptional Induction of ADAMTS5 Protein by Nuclear Factor-κB (NF-κB) Family Member RelA/p65 in Chondrocytes during Osteoarthritis Development

“…Taken together, RelA/p65 and ADAMTS5 do not function in a one-to-one correspondence fashion. In fact, the global knock-out mice of Rela are embryonically lethal due to liver dysfunction (48), whereas those of Adamts5 exhibit minor abnormality with digit fusion and valve anomalies under physiological conditions (49,50).…”

Myocardial Extracellular Matrix

“…Studies regarding the functions of versican in the heart show that it is a much needed component in cardiac ECM during cardiac development 66,67,101,102 and may be involved in the pathogenesis of valvular disease. [102][103][104] Unfortunately, not much is known regarding the specific functions of versican in conditions associated with cardiac remodeling, such as MI, angiotensin-induced cardiac hypertrophy, aging, or myocarditis. However, versican may exert important actions on the remodeling heart by modulating cytokine and growth factor responses and through interactions with other components of the ECM.…”