Exogenous PTHrP Repairs the Damaged Fracture Healing of PTHrP+/- Mice and Accelerates Fracture Healing of Wild Mice.

Yinhe Wang,Congzhu Ding,Anlong Liu,Chun Wang,Lei Wang,Hua Lin,Xin Fang,Yang Cao

doi:10.3390/ijms18020337

Abstract

Bone fracture healing is a complicated physiological regenerative process initiated in response to injury and is similar to bone development. To demonstrate whether an exogenous supply of parathyroid hormone–related protein (PTHrP) helps in bone fracture healing, closed mid-diaphyseal femur fractures were created and stabilized with intramedullary pins in eight-week-old wild-type (WT) PTHrP+/+ and PTHrP+/− mice. After administering PTHrP for two weeks, callus tissue properties were analyzed at one, two, and four weeks post-fracture (PF) by various methods. Bone formation–related genes and protein expression levels were evaluated by real-time reverse transcriptase–polymerase chain reaction and Western blots. At two weeks PF, mineral density of callus, bony callus areas, mRNA levels of alkaline phosphatase (ALP), type I collagen, Runt-related transcription factor 2 (Runx-2), and protein levels of Runx-2 and insulin-like growth factor-1 decreased in PTHrP+/− mice compared with WT mice. At four weeks PF, total collagen-positive bony callus areas, osteoblast number, ALP-positive areas, and type I collagen-positive areas all decreased in PTHrP+/− mice. At both two and four weeks PF, tartrate-resistant acid phosphatase–positive osteoclast number and surface decreased a little in PTHrP+/− mice. The study indicates that exogenous PTHrP provided by subcutaneous injection could redress impaired bone fracture healing, leading to mutation of activated PTHrP by influencing callus areas, endochondral bone formation, osteoblastic bone formation, and bone turnover.

Highlights

Bone fracture healing is a complicated physiological regenerative process initiated in response to injury and is similar to bone development
The current study suggests that endogenous parathyroid hormone–related protein (PTHrP) affects bone BMD and shows that BMD increased after injecting PTHrP at one, two, and four weeks (Figure 1), the PTHrP levels within the bone microenvironment might be critical in influencing bone mass acquisition [25]
The present study demonstrated that osteoclastic bone resorption or the tartrate-resistant acid phosphatase (TRAP)-positive osteoclast number and surface decreased in endogenous PTHrP-deficient mice compared with WT mice (Figure 5)

Summary

Introduction

Bone fracture healing is a complicated physiological regenerative process initiated in response to injury and is similar to bone development. Bone fracture healing has been recognized as a long-term process of ossification and remodeling subsequent to hematoma formation, inflammatory response, and cell proliferation and differentiation [2]. Despite present improvements in fracture management, delayed union and nonunion remnants are still incurable complications following surgical reduction and fixation of bone fractures. Autogenous bone graft has been attested to be the gold standard for treating delayed fracture union, but it is accompanied with multiple complications [4,5]. Nonsurgical methods, such as drug use, are considered to facilitate osteogenesis and, to revitalize the healing process when a delayed union occurs [6,7]. Many biological factors have been noted to promote bone fracture healing, and more factors such as vascular endothelial growth factor, bone morphogenetic proteins, macrophage colony-stimulating factor, and transforming growth factor-β 1 were reported to modulate the fracture healing process [8,9,10]

Methods

Results

Conclusion