Loss of Aebp1 function in osteoprogenitor cells leads to skeletal defects resembling Ehlers-Danlos Syndrome by diminishing Wnt/beta-catenin signaling (PRJCA046260)
Ehlers-Danlos Syndrome, Classic-Like, 2 (clEDS2) is a rare genetic disorder caused by biallelic mutations in the AEBP1 gene, which encodes Aortic carboxypeptidase-like protein (ACLP). Patients with clEDS2 exhibit hallmark features such as loose connective tissues, osteoporosis, and scoliosis. Despite its clinical significance, the molecular mechanisms underlying AEBP1 mutations in skeletal development remain poorly understood, and effective therapeutic strategies are currently unavailable.. Here, using OsxCre conditional knockout mice, we show that Aebp1 deletion in osteoprogenitors reduces body size and bone mass, recapitulating key skeletal features reported in clEDS2. In primary osteoblasts, both genetic deletion and siRNA-mediated knockdown of Aebp1 impair osteoblast differentiation. Mechanistically, Aebp1 loss attenuates Wnt/ß-catenin signaling in bone. Restoration of Wnt/ß-catenin signaling by injecting BIO, a small molecule inhibitor of GSK3, significantly rescued bone mass reduction in Aebp1 knockout mice. These findings establish the crucial function of Aebp1 in sustaining Wnt/ß-catenin signaling in bone development. These finding support a model in which Aebp1 sustains baseline Wnt/ß-catenin tone in osteoblast-lineage cells and suggest that Wnt-targeted approaches may help mitigate clEDS2-related skeletal defects.