Bone-targeted delivery of TGF-β type 1 receptor inhibitor rescues uncoupled bone remodeling in Camurati-Engelmann disease.

Camurati-Engelmann disease (CED) is a genetic bone-modeling disorder mainly caused by mutations in the gene that encodes transforming growth factor-β1 (TGF-β1). Symptoms of CED include bone pain, fractures, and dysplasia. Currently, effective therapies for bone fracture and dysplasia in CED are urgently needed. We have demonstrated that TGF-β1 is a coupling factor for bone remodeling and is aberrantly activated in CED. Daily injection of TGF-β type 1 receptor inhibitor (TβR1I) attenuated CED symptoms, but this systemic administration caused serious side effects. In this study, we created a conjugate linking TβR1I and alendronate, which delivered TβR1I specifically to bone. After weekly injection of the conjugate for 8 weeks, normal bone morphology and remodeling in CED mice was maintained with a minimum effective dose 700 times lower than TβR1I injection. Additionally, we found that the conjugate restored normal bone turnover by reducing the number of osteoblasts and osteoclasts, maintained a regular osteogenic microenvironment by regulating the formation of CD31 and Endomucin double-positive vessels, and preserved ordinary bone formation via inhibition of the migration of leptin-receptor-positive cells. Thus, targeting delivery of TβR1I to bone is a promising therapy for CED and other uncoupled bone remodeling disorders.