Bone Reinnervation After Fracture: A Study in the Rat

Abstract

Reinnervation after tibial fracture in the rat was studied by analyzing the occurrence of growth-associated protein 43 (GAP-43), a marker for regenerating nerve fibers, and protein gene product 9.5 (PGP-9.5), a marker for mature nerve fibers, by immunohistochemistry. At 3 days postfracture, GAP-43--immunoreactive nerve fibers were first observed in the fracture hematoma and periosteum. At 7 days postfracture, abundant sprouting of GAP-43--positive fibers was seen in the callus, hyperplastic periosteum, and edge of fibrocartilage. In the latter region, the nerve fibers were nonvascular, showing dense ramifications and terminal sprouting close to chondroid cells. At 14 days and 21 days postfracture, many GAP-43--positive fibers were still sprouting into the fibrocartilage and new woven bone. Fine varicose GAP-43--positive fibers also were present in the bone marrow. In contrast to GAP-43, PGP-9.5-positive nerve fibers were observed only occasionally at 3 days postfracture but gradually increased in number from day 14 to 21. Our study shows that intense nerve regeneration occurs in early fracture healing partly unrelated to neovascularization. Considering that neuronal mediators have been shown to participate in local bone formation and resorption, the nerve regeneration observed may prove to be essential for delivery of neuronal mediators required for normal callus formation and/or neovascularization.

Neuronal pathways in tendon healing and tendinopathy - update

“…GAP may be involved in nerve regeneration by regulating growth cone motility and axon guidance signals (107). These observations of early nerve regeneration are in line with observations on bone, ligament and skin healing indicating that nerve ingrowth is a fundamental aspect of tissue healing (22,(108)(109)(110)(111).…”

Development of Rat Tibia Innervation: Colocalization of Autonomic Nerve Fiber Markers with Growth-Associated Protein 43

“…In our hands, GAP-43 appeared to be a superior marker of growing nerve fibers since it allowed earlier detection of bone-related nerve fibers than PGP 9.5 [Gajda et al, 2005;Li et al, 2001]. Moreover, the disappearance of GAP-43-immunoreactive fibers in later stages of the development may reflect nerve fiber maturation (PGP 9.5 remains).…”

“…First, GAP-43-IR nerve fibers can be found in the fracture hematoma and in the periosteum as early as 3 days after experimental fracture of rat tibia [Li et al, 2001]. PGP 9.5-IR fibers were present 1 week post-trauma, and within 14 days CGRP-containing fibers were observed in the periosteum [Hukkanen et al, 1993].…”

“…Protein gene product 9.5 (PGP 9.5, PGP), which belongs to a group of ubiquitin hydrolases, is a panneuronal marker and it has also been used in such investigations [Gajda et al, 2005;Sisask et al, 1995Sisask et al, , 1996. In the case of regenerating peripheral nerves, GAP-43-immunoreactive fibers appeared earlier than fibers immunostained for general panneuronal marker PGP 9.5 [Li et al, 2001;Verze et al, 2003]. Sensory and autonomic neuromediators were found in nerve fibers of mature bone [Bjurholm et al, 1988a[Bjurholm et al, , 1988b.…”

Effects of Medulla Spinalis Injury on Fracture Healing

“…Bunun olası nedenleri arasında çalışmamızda planladığımız deney süresinin, kırıkta tam iyileşme oluşturmaya yetmemesi olabilir. Sıçanlarda iyileşmenin değerlendirilmesi için operasyon sonrası 4-5 hafta bekleyen çalışmalar olduğu gibi daha uzun dönem sonuçların yayınlandığı çalışmalarda bulunmaktadır [11,12,14,15,19,31]. İnsanlar üzerinde yapılan geriye dönük çalışmalarda da spinal travmanın kemik üzerinde ciddi bir yıkıma neden olduğu gösterilmiştir [17,19].…”