Mechanobiology of the Intervertebral Disc and Relevance to Disc Degeneration

Abstract

Mechanical loading of the intervertebral disc may contribute to disc degeneration by initiating degeneration or by regulating cell-mediated remodeling events that occur in response to the mechanical stimuli of daily activity. This article is a review of the current knowledge of the role of mechanical stimuli in regulating intervertebral disc cellular responses to loading and the cellular changes that occur with degeneration. Intervertebral disc cells exhibit diverse biologic responses to mechanical stimuli, depending on the loading type, magnitude, duration, and anatomic zone of cell origin. The innermost cells respond to low-to-moderate magnitudes of static compression, osmotic pressure, or hydrostatic pressure with increases in anabolic cell responses. Higher magnitudes of loading may give rise to catabolic responses marked by elevated protease gene or protein expression or activity. The key regulators of these mechanobiologic responses for intervertebral disc cells will be the micromechanical stimuli experienced at the cellular level, which are predicted to differ from that measured for the extracellular matrix. Large hydrostatic pressures, but little volume change, are predicted to occur for cells of the nucleus pulposus during compression, while the highly oriented cells of the anulus fibrosus may experience deformations in tension or compression during matrix deformations. In general, the pattern of biologic response to applied loads suggests that the cells of the nucleus pulposus and inner portion of the anulus fibrosus experience comparable micromechanical stimuli in situ and may respond more similarly than cells of the outer portion of the anulus fibrosus. Changes in these features with degeneration are critically understudied, particularly degeneration-associated changes in cell-level mechanical stimuli and the associated mechanobiology. Little is known of the mechanisms that regulate cellular responses to intervertebral mechanobiology, nor is much known with regard to the precise mechanical stimuli experienced by cells during loading. Mechanical factors appear to regulate responses of the intervertebral disc cells through mechanisms involving intracellular Ca(2+) transients and cytoskeletal remodeling that may regulate downstream effects such as gene expression and posttranslational biosynthesis. Future studies should address the broader biologic responses to mechanical stimuli in intervertebral disc mechanobiology, the involved signaling mechanisms, and the apparently important interactions among mechanical factors, genetic factors, cytokines, and inflammatory mediators that may be critical in the regulation of intervertebral disc degeneration.

Activation of TonEBP by Calcium Controls β1,3-Glucuronosyltransferase-I Expression, a Key Regulator of Glycosaminoglycan Synthesis in Cells of the Intervertebral Disc

“…Predictably, at both the mRNA and protein level, there was robust expression of GlcAT-I in nucleus pulposus cells of both the neonatal and mature rat discs; the protein was also expressed by cells of the annulus fibrosus. This latter observation was not unexpected, since the inner annulus, like the nucleus, is rich in proteoglycans (1,2). Gain and loss of function experiments were performed to learn if calcium flux induced transcriptional activation of GlcAT-I reporter activity and if this activation was regulated by TonEBP.…”

“…Although sparse, cells in the nucleus pulposus secrete a complex extracellular matrix that contains fibrillar collagens and the proteoglycan aggrecan. Glycosoaminoglycan (GAG) 2 components of the aggrecan molecule provide a robust hydrodynamic system that serves to accommodate applied biomechanical forces (1,2). Surprisingly, although the importance of aggrecan secretion and function has been discussed by many investigators, mechanisms of control of GAG synthesis are poorly understood.…”

Intervertebral disc degeneration in a naturally occurring primate model: Radiographic and biomechanical evidence

“…Lumbar intervertebral discs change morphologically, biochemically, and biomechanically with advancing age, [1][2][3][4][5][6][7][8][9][10] changes that are characterized as disc degeneration and are implicated as the origin of low back pain. Unfortunately, the initiating and perpetuating factors of disc degeneration are unknown, so despite the pain, disability, and economic loss associated with disc degeneration, intervention and mitigation strategies cannot effectively proceed.…”

Discogenic pain: Who cares?

“…This hypothesis is supported by experimental animal models [25][26][27] and epidemiological data, linking heavy lifting, intense physical work, and obesity with increaseing rates of LBP [28][29][30]. Supra-physiologic movements like bending, rotation, and compression can lead to structural defects associated with degeneration of the IVD [31]. A recent study has also shown that intense physical stress can induce a catabolic response characterized by increasing protease gene and protein expression/activity [32].…”