Innervation is higher above Bone Remodeling Surfaces and in Cortical Pores in Human Bone: Lessons from patients with primary hyperparathyroidism

Abstract

Mounting evidence from animal studies suggests a role of the nervous system in bone physiology. However, little is known about the nerve fiber localization to human bone compartments and bone surface events. This study reveals the density and distribution of nerves in human bone and the association of nerve profiles to bone remodeling events and vascular structures in iliac crest biopsies isolated from patients diagnosed with primary hyperparathyroidism (PHPT). Bone sections were sequentially double-immunostained for tyrosine hydroxylase (TH), a marker for sympathetic nerves, followed by protein gene product 9.5 (PGP9.5), a pan-neuronal marker, or double-immunostained for either PGP9.5 or TH in combination with CD34, an endothelial marker. In the bone marrow, the nerve profile density was significantly higher above remodeling surfaces as compared to quiescent bone surfaces. Ninety-five percentages of all nerve profiles were associated with vascular structures with the highest association to capillaries and arterioles. Moreover, vasculature with innervation was denser above bone remodeling surfaces. Finally, the nerve profiles density was 5-fold higher in the intracortical pores compared to bone marrow and periosteum. In conclusion, the study shows an anatomical link between innervation and bone remodeling in human bone.

The Role of Nerves in Skeletal Development, Adaptation, and Aging

“…Nonetheless, innervation of bone is most dense in the periosteum and marrow spaces, with relatively few nerves present in the mineralized bone ( 9 , 10 ). Furthermore, innervation density is increased at sites nearest to active bone remodeling surfaces ( 20 ).…”

Functional Biomaterials for Bone Regeneration: A Lesson in Complex Biology

“…In support of a clear association of nerves with bone metabolism, a recent study reported the presence of higher innervation density at the surface of bone remodeling in the iliac crest from patients with hyperparathyroidism. [198] The study further shows the distribution of both sympathetic and nonsympathetic nerves in bone and a higher innervation density present in the intracortical cavities compared to periosteum and bone marrow.…”

Simultaneous Regeneration of Bone and Nerves Through Materials and Architectural Design: Are We There Yet?

“…[ 351,352 ] Much of bone's innervation is centripetally distributed, derived from periosteal fibers that branch within the compact bone and bone marrow. [ 19,353–355 ]…”

“…They are distributed throughout the skeletal tissues, including the periosteum and bone marrow. [ 19–21 ] Bone is richly innervated by peripheral sensory and motor nerves, which transport different excitation signals and covey information to the targeted cells or tissues. [ 22,23 ] Unlike vascularization, the process of nerve repair in bone defects is obscure, with no visibly‐discernible influence on short‐term healing.…”