Figure 1. Skeletal interoception in healthy and diseased bone conditions. In the healthy state, when bone mass decreases, osteoblasts and bone cells release PGE2, activating EP4 on sensory nerves, and ascending signals are sent from bone tissue via sensory nerves, dorsal root ganglia, and superficial dorsal horns of the spinal cord to the CNS (green arrows), specifically in the hypothalamus. After interpretation, descending signals from the CNS regulate bone and adipose metabolism via neuroendocrinal regulation through NPY and the sympathetic nervous systems (blue arrows, NE). Bone implants containing Mg2+, Zn2+ and Cu2+ activate osteogenesis also through the PGE2/EP4 pathway. Downregulation of NPY induces preosteoblasts to differentiate into osteoblasts, leading to bone formation rather than to differentiate into adipocytes to grow fat tissue. In bone degenerative conditions such as lower back pain and osteoarthritis, excessive expression of PGE2 results in angiogenesis and innervation via Netrin1 secreted by osteoclasts, and pain from hypersensitivity of sensory nerves by activating EP4 (orange arrows). CNS: central nervous system; EP4: prostaglandin E receptor 4; MSC: mesenchymal stem cell; NE: norepinephrine; NPY: neuropeptide Y; PGE2: prostaglandin E2.