PTH-Induced Bone Regeneration and Vascular Modulation Are Both Dependent on Endothelial Signaling

Abstract

The use of a bone allograft presents a promising approach for healing nonunion fractures. We have previously reported that parathyroid hormone (PTH) therapy induced allograft integration while modulating angiogenesis at the allograft proximity. Here, we hypothesize that PTH-induced vascular modulation and the osteogenic effect of PTH are both dependent on endothelial PTH receptor-1 (PTHR1) signaling. To evaluate our hypothesis, we used multiple transgenic mouse lines, and their wild-type counterparts as a control. In addition to endothelial-specific PTHR1 knock-out mice, we used mice in which PTHR1 was engineered to be constitutively active in collagen-1α+ osteoblasts, to assess the effect of PTH signaling activation exclusively in osteoprogenitors. To characterize resident cell recruitment and osteogenic activity, mice in which the Luciferase reporter gene is expressed under the Osteocalcin promoter (Oc-Luc) were used. Mice were implanted with calvarial allografts and treated with either PTH or PBS. A micro-computed tomography-based structural analysis indicated that the induction of bone formation by PTH, as observed in wild-type animals, was not maintained when PTHR1 was removed from endothelial cells. Furthermore, the induction of PTH signaling exclusively in osteoblasts resulted in significantly less bone formation compared to systemic PTH treatment, and significantly less osteogenic activity was measured by bioluminescence imaging of the Oc-Luc mice. Deletion of the endothelial PTHR1 significantly decreased the PTH-induced formation of narrow blood vessels, formerly demonstrated in wild-type mice. However, the exclusive activation of PTH signaling in osteoblasts was sufficient to re-establish the observed PTH effect. Collectively, our results show that endothelial PTHR1 signaling plays a key role in PTH-induced osteogenesis and has implications in angiogenesis.

A Novel PTH‐Related Peptide Combined With 3D Printed Macroporous Titanium Alloy Scaffold Enhances Osteoporotic Osseointegration

“…[ 22,23 ] Both PTH‐induced bone regeneration and vascular regulation depend on endothelial signal transduction, and when PTHR1 in endothelial cells is knocked out, the formation of PTH‐induced narrow blood vessels is significantly reduced and the osteogenesis of PTH is weakened. [ 24 ] Only inducing the PTH axis in osteoblasts is not enough to induce bone formation. Therefore, promoting angiogenesis is equally important in the repair of osteoporotic bone defects.…”

Effect of intraoral administration of parathyroid hormone on osseous and soft tissue healing around implants in ovariectomized rat maxillae

“…An in vitro study demonstrated that intermittent PTH administration promoted the proliferation and migration of fibroblasts, which contribute to improved wound healing (Shen et al., 2020). In addition, intermittent PTH administration has shown the ability to induce angiogenesis and vascular modulation of small‐diameter blood vessels through the endothelial cell PTHR (Cohn Yakubovich et al., 2017; Cohn‐Schwartz et al., 2022). Moreover, intermittent PTH administration has been reported to stimulate the proliferation and migration of endothelial cells (Shen et al., 2020).…”

Similarities and Differences of Vascular Calcification in Diabetes and Chronic Kidney Disease

“…Recent animal investigations have suggested that the increase of PTH triggers the transformation of aortic endothelial cells into chondrocytes 171 and the PTH receptor 1 (PTHR1) signaling of endothelial cells plays a pivotal role in PTH-induced osteogenesis and is correlated to angiogenesis. 192 It is acknowledged that insulin resistance is closely associated with diabetes, and insulin stimulates the release of endothelial NO, which in turn oxidizes lipoproteins, decelerates the rate of intimal calcification, and suppresses vasa vasorum formation. 128 Upon the occurrence of insulin resistance (IR), the higher concentration of free fatty acids in the liver prompts the body to amplify the absorption and very low-density lipoprotein (VLDL) triglyceride production and secretion to compensate; therefore, the susceptibility to blood vessel calcification escalates.…”