Abstract
The peripheral nervous system modulates bone repair under physiological and pathophysiological conditions. Previously, we reported an essential role for sensory neuropeptide substance P (SP) and sympathetic nerve fibers (SNF) for proper fracture healing and bone structure in a murine tibial fracture model. A similar distortion of bone microarchitecture has been described for mice lacking the sensory neuropeptide α-calcitonin gene-related peptide (α-CGRP). Here, we hypothesize that loss of SP, α-CGRP, and SNF modulates inflammatory and pain-related processes and also affects bone regeneration during fracture healing under postmenopausal conditions. Intramedullary fixed femoral fractures were set to 28 days after bilateral ovariectomy (OVX) in female wild type (WT), SP-, α-CGRP-deficient, and sympathectomized (SYX) mice. Locomotion, paw withdrawal threshold, fracture callus maturation and numbers of TRAP-, CD4-, CD8-, F4/80-, iNos-, and Arg1-positive cells within the callus were analyzed. Nightly locomotion was reduced in unfractured SP-deficient and SYX mice after fracture. Resistance to pressure was increased for the fractured leg in SP-deficient mice during the later stages of fracture healing, but was decreased in α-CGRP-deficient mice. Hypertrophic cartilage area was increased nine days after fracture in SP-deficient mice. Bony callus maturation was delayed in SYX mice during the later healing stages. In addition, the number of CD 4-positive cells was reduced after five days and the number of CD 8-positive cells was additionally reduced after 21 days in SYX mice. The number of Arg1-positive M2 macrophages was higher in α-CGRP-deficient mice five days after fracture. The alkaline phosphatase level was increased in SYX mice 16 days after fracture. Absence of α-CGRP appears to promote M2 macrophage polarization and reduces the pain threshold, but has no effect on callus tissue maturation. Absence of SP reduces locomotion, increases the pain-threshold, and accelerates hypertrophic callus tissue remodeling. Destruction of SNF reduces locomotion after fracture and influences bony callus tissue remodeling during the later stages of fracture repair, whereas pain-related processes are not affected.
Highlights
A network of sensory and sympathetic nerve fibers can be observed throughout bone tissue, innervating cortical and trabecular bone, the bone marrow, and the periosteum
Locomotion was reduced in SYX mice 5, 9, and 21 days after fracture when compared to wild type (WT) control animals (Figure 1B)
In an in vitro study, we demonstrated that the absence of substance P (SP) reduced the number of osteoclast-precursor cells and the differentiation capacity to mature osteoclasts, but no differences were observed in osteoclast number in untreated bones of Tac1−/− compared to WT mice [39]
Summary
A network of sensory and sympathetic nerve fibers can be observed throughout bone tissue, innervating cortical and trabecular bone, the bone marrow, and the periosteum. Neurotransmitters from these nerve fibers are critically involved in the control of vascularization, bone development, and bone growth. Neurotransmitter signaling has been shown to influence bone regeneration during fracture healing [3] and is involved in cartilage and subchondral bone alterations during disease progression of osteoarthritis [4]. Ding et al described poorer fracture healing and a decrease of SP at the injury site after femoral shaft fractures in ovariectomized (OVX) mice compared to control mice [8], suggesting a critical role of this neuropeptide during bone repair, under physiological conditions, and under pathophysiological conditions
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