Signaling in response to hypoxia and normoxia in the intervertebral disc

Adele L. BoskeyDisc disease is a major cause of disability, with 300,000 individuals per year undergoing discectomyprocedures in the US (1). Low back pain has beenassociated with degeneration of the disc, and in partic-ular with loss of proteoglycan (aggrecan) production inthe center of the disc (2). Not everyone with back painundergoes a discectomy; thus, the incidence of discproblems is likely to be much higher than the 300,000per year. With this high incidence, it is amazing that fewstudies (16 indexed in PubMed [3–18] at the time ofwriting) have addressed how molecular signals are con-veyed to the center of the disc, the nucleus. In fact, mostof the molecular studies on the nucleus pulposus arefocused either on the initial development of the disc (6)or on how drugs act on the diseased disc (8), rather thanon the innate properties of the healthy disc or the abilityof the nucleus to respond to changes in its environment.The functions of the intervertebral discs, whichseparate the vertebrae, include load bearing and permit-ting mobility of what otherwise would be a rigid spine(19). The intervertebral disc consists of an outer ring oflamellar collagen fibrils (the annulus) surrounding thegel-like nucleus pulposus. These structures are cappedby cartilaginous end plates. The blood supply to the discis only to the end plates. The 3 tissue types (end plates,annulus, and nucleus) work together, but have distinctfunctions. The nucleus not only has mechanical(swelling/compressive) properties, but also provides nu-trition for the tissue. In healthy spines the nucleuspulposus maintains a fixed volume while undergoingdeformation. With disease, the hydration of the nucleusis lost, and the disc loses its compressive properties andalso loses height, which affects adjacent ligamentousstructures, and these events result in back pain (20).The nucleus is a highly avascular tissue with noindependent blood supply; in fact, it is considered themost avascular structure in the body (21). It also has alower cellularity than articular cartilage (21). In thepresence of low oxygen tension, low pH, and low levelsof glucose, most energy for the nucleus pulposus isderived from anaerobic glycolysis rather than from oxi-dativephosphorylation(22);thus,itisnotsurprisingthathypoxia-inducible factors (HIF-1 , HIF-2 ) are ex-pressed in this tissue (23–25). HIF-1 is also expressedin articular (26,27) and growth plate (28) cartilages.