Combined ADAMTS10 and ADAMTS17 inactivation exacerbates bone shortening and skin phenotypes

ABSTRACT: Weill-Marchesani syndrome (WMS) is characterized by severe short stature, in particular short hands and feet (brachydactyly), joint contractures, tight skin, and heart valve, eye, and skin anomalies. Whereas recessive WMS is caused by mutations in ADAMTS10, ADAMTS17, or LTBP2 (all recessive), dominant WMS is caused by FBN1 (encoding fibrillin-) mutations. Since bone growth is driven by chondrocyte proliferation and hypertrophy in the growth plates, the genetics of WMS suggests that the affected ECM proteins act within the same pathway to regulate chondrocyte and growth plate function. Here, we investigated the role of the secreted ADAMTS proteases, ADAMTS10 and ADAMTS17 in growth plate function and ECM formation. We generated Adamts10;Adamts17 double knockout (DKO) mice, which showed significant postnatal lethality compared to Adamts10 or Adamts17 KO mice. Importantly, we observed severe bone shortening DKO mice, which correlated with a narrower hypertrophic zone in their growth plates. ADAMTS17 substrates were sought by N-terminomics and interacting partners by yeast two-hybrid screens screening. Surprisingly, validation experiments did not reveal direct proteolysis of either fibronectin or COL6 by ADAMTS17. We then investigated ECM formation in primary ADAMTS10- and ADAMTS17-deficient skin fibroblasts and observed compromised fibronectin deposition concomitant with aberrant intracellular accumulation of fibrillin-1. These findings support a role for ADAMTS17 in ECM protein secretion and assembly. Collectively, our data suggest that ADAMTS10 and ADAMTS17 regulate bone growth, by regulating chondrocyte hypertrophy or hypertrophic chondrocyte turnover. ADAMTS17 appears to be a critical regulator of ECM protein secretion or pericellular assembly, whereas ADAMTS10 likely modulates ECM formation at later stages, possibly specifically the deposition or isoform composition of fibrillin.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Fibroblast

DISEASE(S): Weill-marchesani Syndrome

SUBMITTER: Daniel Martin  

LAB HEAD: Dirk Hubmacher

PROVIDER: PXD068317 | Pride | 2025-09-30

REPOSITORIES: Pride