Neuro-Immuno-Endocrine Regulation of Bone Homeostasis

Bone is an important connective tissue involved in the movement and mechanical support of the body. Its homeostasis refers to the equilibrium between bone formation by osteoblasts and bone resorption by osteoclasts. Hematopoietic progenitor cells are shared by bone and immune cells, and the skeletal system is extensively innervated by an extensive nerve network. The immune, endocrine and nervous systems synthesize and secrete cytokines, hormones and neurotransmitters, respectively, which regulate physiological processes involved in bone homeostasis. Hormones such as gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen, testosterone, insulin, thyroxine, parathyroid hormone (PTH), calcitonin, etc., regulate bone formation and resorption. Tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin (interleukin (IL)-1,3,4,6,10,17,18,23,27) regulate the function of osteoblasts and osteoclasts as well as the bone microenvironment. The skeleton is innervated by sympathetic, parasympathetic and sensory nerve fibers that release neurotransmitters/factors such as serotonin, nerve growth factor, neuropeptide Y, substance P, norepinephrine and acetylcholine, which interact with various cells in the bone. Sclerostin, osteopontin, osteoprotegerin, osteocalcin, prostaglandin E2 and receptor activator of nuclear factor-kappa B ligand (RANKL)/receptor activator of nuclear factor-kappa B (RANK) are some of the important proteins released by osteoblasts, osteocytes and osteoclasts that regulate osteoblastogenesis, osteoclastogenesis and angiogenesis and are also involved in pathological conditions. Further research is needed to establish links between the skeleton and other tissues and to gain additional insights into the etiology of degenerative diseases and the drug development process. The aim of this minireview is therefore to understand the composition of bone and the maintenance of bone homeostasis through three coordinates, namely the endocrine, nervous and immune systems.