Figure 1.

Factors that contribute to activation of peripheral bone marrow nociceptors. Mast cells and macrophages, and cells associated with various different types of tumor in bone, release cytokines, interleukins, growth factors (including NGF), and other inflammatory mediators (represented by red circles). These act directly on the peripheral nerve terminal endings of sensory neurons that innervate the bone marrow. Destruction of bone by osteolytic processes as well as excessive mechanical stress or trauma can also lead to injury or distortion of bone that activates mechanically sensitive bone marrow nociceptors. Osteoclast-mediated bone remodeling and osteolytic tumors are accompanied by the production of extracellular protons (represented by blue circles) which are known to activate nociceptors in other tissues and likely also do so in bone marrow.