Targeted activation of androgen receptor signaling in the periosteum improves bone fracture repair

Kuo-Chung Lan,Ching-Chen Lin,Pei-Ling Won,Ya-Fen Liu,Jia-Feng Chen,Bi-Hua Cheng,Kuo-Ting Wei,Tien-Min G Chu,Ko-En Huang,Chawnshang Chang,Pei-Wen Lin,Hong-Yo Kang,Yun-Ju Chen

doi:10.1038/s41419-022-04595-1

Abstract

Low testosterone level is an independent predictor of osteoporotic fracture in elderly men as well as increased fracture risk in men undergoing androgen deprivation. Androgens and androgen receptor (AR) actions are essential for bone development and homeostasis but their linkage to fracture repair remains unclear. Here we found that AR is highly expressed in the periosteum cells and is co-localized with a mesenchymal progenitor cell marker, paired-related homeobox protein 1 (Prrx1), during bone fracture repair. Mice lacking the AR gene in the periosteum expressing Prrx1-cre (AR-/Y;Prrx1::Cre) but not in the chondrocytes (AR-/Y;Col-2::Cre) exhibits reduced callus size and new bone volume. Gene expression data analysis revealed that the expression of several collagens, integrins and cell adhesion molecules were downregulated in periosteum-derived progenitor cells (PDCs) from AR-/Y;Prrx1::Cre mice. Mechanistically, androgens-AR signaling activates the AR/ARA55/FAK complex and induces the collagen-integrin α2β1 gene expression that is required for promoting the AR-mediated PDCs migration. Using mouse cortical-defect and femoral graft transplantation models, we proved that elimination of AR in periosteum of host mice impairs fracture healing, regardless of AR existence of transplanted donor graft. While testosterone implanted scaffolds failed to complete callus bridging across the fracture gap in AR-/Y;Prrx1::Cre mice, cell-based transplantation using DPCs re-expressing AR could lead to rescue bone repair. In conclusion, targeting androgen/AR axis in the periosteum may provide a novel therapy approach to improve fracture healing.

Highlights

Bone repair after fracture is a complex process in which the periosteum is stimulated to form a cartilaginous callus, which subsequently undergoes bone regeneration [1]
We elucidate the novel genomic and nongenomic androgen receptor (AR) actions on PDCs to accelerate bone callus formation in mouse femoral defect models via promoting collagen-integrin expression and interaction to activate AR/ARA55/FAK axis, increasing the transduction of androgen signaling to focal adhesion complex in regulating PDCs migrated to the site of skeletal injury (Fig. 7)
Androgens stimulate periosteal bone formation in both men and male rodents [41, 42] and are known to have a direct effect on bone healing, as it induced callus formation in segmental bone defect mouse models [43], which are in line with our present results that male mice lacking AR (AR-/Y;Prrx1::Cre) have decreased periosteal cell activity with low levels of collagens and integrins and testosterone can only promote bone fracture repair in ARflox/Y control mice, but not in AR-/Y;Prrx1::Cre mice

Summary

INTRODUCTION

Bone repair after fracture is a complex process in which the periosteum is stimulated to form a cartilaginous callus, which subsequently undergoes bone regeneration [1]. In contrast to targeted deletion of AR gene in osteoprogenitors [26], mature the expression pattern that of the TM4 Sertoli cell line, these Rosaosteoblasts [27] or osteocytes [28] only have lower cancellous positive PDCs expressed periostin, a key regulator of periosteal bone mass, but no the cortical phenotype, the role for AR in cells with high bone regenerative potential in the periosteum and cortical fracture repair remains to be determined We sought their stem cell niche [30], as well as Prrx, fibroblast growth factor to investigate whether the actions of androgen/AR signaling in receptor 3 and fibroblast growth factor 18, markers of periosteal.

RESULTS

DISCUSSION

Findings

METHODS