Aebp1 loss in osteoprogenitors leads to skeletal defects resembling Ehlers-Danlos Syndrome by diminishing Wnt/β-catenin signaling

TL;DR

Deleting Aebp1 in bone-forming cells causes skeletal issues similar to a rare genetic disorder, and restoring a specific signaling pathway can reverse these effects.

Contribution

This study reveals that Aebp1 maintains Wnt/β-catenin signaling in bone cells and suggests targeting this pathway could treat related skeletal disorders.

Findings

Aebp1 deletion in osteoprogenitors causes reduced bone mass and body size in mice.

Aebp1 loss impairs osteoblast differentiation and reduces Wnt/β-catenin signaling.

Restoring Wnt/β-catenin signaling with BIO rescues bone mass in Aebp1-deficient mice.

Abstract

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 KO 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/β-catenin signaling in bone. Restoration of Wnt/β-catenin signaling by injecting BIO, a small molecule inhibitor of GSK3, substantially rescued bone mass reduction in Aebp1-KO mice. These findings support a model in which Aebp1 sustains baseline Wnt/β-catenin tone in osteoblast-lineage cells and suggest that Wnt-targeted approaches may help mitigate clEDS2-related skeletal defects.

AEBP1 regulates bone development via Wnt/β-catenin signaling. Restoring Wnt/β-catenin signaling pathway alleviates skeletal defects in clEDS2. Offering potential therapeutic strategies for related bone disorders.

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