Abstract
Mechanical stimulation is known to influence intervertebral disc (IVD) cell behavior and function, but the effect on disc cells is routinely considered in isolation from other microenvironmental factors. Acidic pH has been shown to be a prominent and detrimental microenvironmental factor present in degenerate IVDs, but its influence on the human disc cell mechanoresponse has never been studied. We investigated the response of agarose‐encapsulated human nucleus pulposus (NP) cells to 0.004 MPa, 1.0 Hz and 1 hour of compression (Flexcell FX4000 Compression System) under pH conditions representative of nondegenerate (pH 7.1) and degenerate (pH 6.5) IVDs. Cell viability, extracellular matrix production, and expression of anabolic/anti‐catabolic and catabolic genes were assessed. We report that preculture of NP cells in agarose gels was required in order for cells to be mechanoresponsive, and this correlated with increased type VI collagen, α5β1 integrin, and fibronectin expression. Furthermore, the matrix homeostatic response observed at pH 7.1 (representative of nondegenerate IVDs; increased aggrecan [AGC], tissue inhibitor of metalloproteinases‐1 [TIMP1], matrix metalloproteinase‐3 [MMP3], a disintegrin and metalloproteinase with thrombospondin motif‐5 [ADAMTS5] gene expression) was RGD‐integrin dependent, whereas only MMP3 remained mechanoresponsive at pH 6.5, and this was independent of RGD‐integrins. Our findings suggest differential mechanotransduction pathways operating for specific genes, with RGD‐integrin dependent AGC expression, but not RGD‐independent MMP3 expression, inhibited at pH representative of degenerate IVDs (pH 6.5), which could contribute to the catabolic phenotype observed during IVD degeneration.Clinical significanceCharacterizing the influence of the mechanical and chemical intervertebral disc microenvironment on disc cells, particularly in disc degeneration, could help develop future therapeutic strategies for the treatment of discogenic back pain.
Highlights
The intervertebral disc (IVD) is a fibrocartilage pad located between motion segments in the spine
In addition to assessing the mechanoresponse of nucleus pulposus (NP) cells to compression at pH representative of IVDs in health and disease, we investigated the mechanotransduction pathways operating in NP cells under these conditions
Mechanical stimuli are known to be important for IVD cell matrix homeostasis, but the mechanotransduction pathways utilized by disc cells remain poorly understood
Summary
The intervertebral disc (IVD) is a fibrocartilage pad located between motion segments in the spine. The healthy IVD facilitates flexion and rotation of the spine through all planes while maintaining stability[1] and is predicted to experience mechanical compressive loads in excess of 2.3 MPa (depending on the activity).[2,3] The mechanical compressive forces are transduced to the resident cells, both directly through the coupling of cell surface receptors and the extracellular matrix (ECM) and indirectly through compression-induced changes to the ECM, including changes in osmotic pressure, fixed charge density, and extracellular pH.[4] The pericellular matrix, characterized as a type VI collagen and perlecan-rich matrix immediately proximal to the cell,[5,6] has been shown to play an important role in transducing mechanical force from the surrounding tissue to the cell surface.[7]. Increasing our understanding of how disc cells respond to mechanical stimuli both in health and disease will help further our knowledge of the pathophysiology of IVD degeneration and potentially lead to the identification of novel therapeutic targets for its treatment
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