Activation of CGRP receptor–mediated signaling promotes tendon-bone healing

Abstract

Calcitonin gene-related peptide (CGRP), an osteopromotive neurotransmitter with a short half-life, shows increase while calcitonin receptor-like (CALCRL) level is decreased at the early stage in bone fractures. Therefore, the activation of CALCRL-mediated signaling may be more critical to promote the tendon-bone healing. We found CGRP enhanced osteogenic differentiation of BMSCs through PKA/CREB/JUNB pathway, contributing to improved sonic hedgehog (SHH) expression, which was verified at the tendon-bone interface (TBI) in the mice with Calcrl overexpression. The osteoblast-derived SHH and slit guidance ligand 3 were reported to favor nerve regeneration and type H (CD31 hi EMCN hi ) vessel formation, respectively. Encouragingly, the activation or inactivation of CALCRL-mediated signaling significantly increased or decreased intensity of type H vessel and nerve fiber at the TBI, respectively. Simultaneously, improved gait characteristics and biomechanical performance were observed in the Calcrl overexpression group. Together, the gene therapy targeting CGRP receptor may be a therapeutic strategy in sports medicine.

Impaired Tertiary Dentin Secretion after Shallow Injury in Tgfbr2-Deficient Dental Pulp Cells Is Rescued by Extended CGRP Signaling

“…Their results showed striking reductions/increases in mineralization markers and bone volume following the silencing/overexpression of the CGRP receptors, similar to the findings of the orthodontic implant study [99]. This demonstrated that increasing the expression of CGRP receptors at the earlier time points, when CGRP levels peak, dramatically improves bone healing [101]. We hypothesize that the prolonged peak of CGRP in our Tgfbr2 cko mice led to the CGRP being present when the receptor expression levels were higher, which allowed for additional mineralization signals in the absence of Tgfbr2.…”

Impaired Tertiary Dentin Secretion After Shallow Injury in Tgfbr2-Deficient Dental Pulp Cells Is Rescued by Extended CGRP Signaling

“…Their results showed striking reductions/increases in mineralization markers and bone volume following the silencing/overexpression of the CGRP receptors, similar to the findings of the orthodontic implant study [31]. This demonstrated that increasing CGRP receptors at the earlier timepoints when CGRP levels peak dramatically improves bone healing [33]. We hypothesize that the prolonged peak of CGRP in our Tgfbr2 cko mice was present when the receptor expression levels would be higher, which allowed for additional mineralization signals in the absence of Tgfbr2.…”