Combined ADAMTS10 and ADAMTS17 inactivation exacerbates bone shortening and skin phenotypes

Weill–Marchesani syndrome (WMS) is characterized by severe short stature, joint contractures, tight skin, heart valve and eye anomalies. WMS is caused by biallelic mutations in ADAMTS10, ADAMTS17, or LTBP2, or mono-allelic mutations in FBN1. Because bone growth is driven by chondrocyte proliferation and hypertrophy in the growth plates, the genetics of WMS suggests that the affected extracellular matrix (ECM) proteins contribute to chondrocyte and growth plate function. Here, we show that Adamts10;Adamts17 double knockout (DKO) mice have significant postnatal lethality and exacerbated bone shortening, which correlated with a narrower hypertrophic zone in their growth plates. Potential ADAMTS17 substrates identified by N-terminomics and yeast-2-hybrid screening revealed the ECM proteins fibronectin (FN1) and collagen VI (COL6A2). In primary ADAMTS10- and ADAMTS17-deficient skin fibroblasts, fibronectin deposition was impaired concomitant with aberrant intracellular accumulation of fibrillin-1. These findings support a role for ADAMTS17 in ECM protein secretion and assembly. Mechanistically, ADAMTS17 appears to be a critical regulator of ECM protein secretion or pericellular matrix assembly, whereas ADAMTS10 likely modulates ECM formation at later stages.The data sets for the stylopodial and zeugopodial elements are deposited in the Gene Expression Omnibus repository under the accession numbers GSE252289 (human long bone skeleton ATAC-seq) and GSE252288 (human long bone skeleton RNA-seq). The data sets for the autopodial elements were deposited in the Gene Expression Omnibus repository under the accession numbers GSE283854 and GSE286924. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the data set identifier PXD068317 (Perez-Riverol et al, 2025).