The roles of the nerve-immune axis in modulating bone regeneration

Bone is highly innervated, and its regeneration is significantly nerve-dependent. Extensive evidence suggests that the nervous system plays an active role in bone metabolism and development by modulating osteoblast and osteoclast activity. However, the majority of research to date has focused on the direct effects of peripheral nerves and their neurotransmitters on bone regeneration. Emerging studies have begun to reveal a more intricate role of nerves in regulating the immune microenvironment, which is crucial for bone regeneration. This review summarizes how nerves influence bone regeneration through modulation of the immune microenvironment. We first discuss the changes in peripheral nerves during the regenerative process. We then describe conduction and paracrine pathways through which nerves affect the osteogenic immune microenvironment, emphasizing nerves, neural factors, and their impacts. Our goal is to deepen the understanding of the nerve-immune axis in bone regeneration. A better grasp of how nerves influence the osteogenic immune microenvironment may lead to new strategies that integrate the nervous, immune, and skeletal systems to promote bone regeneration.