Journal of the American Academy of Regenerative Medicine 2017; volume 1:7203 Abstract The aim of this paper is to review the literature on molecular protein and messenger ribonucleic acid (mRNA) factors involved in intervertebral disc degeneration (IVDD). These elements were categorized basing on the changes in i) cell viability or number, ii) extracellular matrix (ECM) and iii) inflammation. Factors found to influ- ence cell number and viability in IVDD included Fas/FasL, tumor necrosis factor related apoptosis-inducing ligand, death receptor-4/-5, bcl2-like 11, p53 inducible nuclear pro- tein 1, p53/p21 factors, basic fibroblast growth factor and transforming growth factor-β. Factors found to affect IVD ECM included a range of matrix metalloproteinase, metal- loproteinases with thrombospondin motifs, tissue inhibitors of metalloproteinases and disintegrins. Several proinflam- matory factors have been identified in IVDD including interleukin-1β and TNF-α. The advent of protein and mRNA detection techniques has increased the understand- ing of IVDD from a molecular perspective. Further study of molecular protein and mRNA factors has the potential to identify and optimize therapeutic targets in the future. Introduction It has been estimated that up to 84% of the global pop- ulation suffers from lower back pain at some point in their lifetime, the most common cause being intervertebral disc (IVD) degeneration (IVDD). 1,2 Recent research has identi- fied current treatments to be less effective than previously thought. 3 This highlights the importance of developing standardized, effective and non-invasive treatments for lower back pain, which requires a thorough understanding of the underlying molecular processes that lead to IVDD. The IVD is composed of three main components, all of which are susceptible to degeneration. In the center lies the non-innervated gelatinous nucleus pulposus (NP), compris- ing of extracellular matrix (ECM) proteins such as proteo- glycans and type II collagen fibers. 4 The NP serves to absorb shock and cushion impact between vertebrae. Surrounding the NP is the annulus fibrosus (AF), which is innervated and contains type I collagen and elastin fibers. 5 The AF facilitates mobility of the spine as well as providing resistance to radial forces from the NP during compressive loading. 6 Finally, cartilaginous end plates (CEP) above and below the AF, as well as the AF itself, modulate diffusion of nutrients between the vertebrae and IVD. 7,8 Vascular supply from the AF to the CEP is present at birth, but by adulthood the IVD undergoes a regression in vascularity. 9 This increases IVD susceptibility to degeneration because the NP ECM degrades without access to sufficient nutrients. The current literature indicates that IVDD is mediated by changes in three major factors: i) cell viability or num- bers, ii) ECM and iii) inflammatory cytokines. 10-14 Although we consider the contributions of these three fac- tors separately, there exists a complex interplay between them, as well as with other local and systemic disease-relat- ed conditions. Collectively, these processes contribute to the progression of IVDD. For example, abnormal produc- tion of inflammatory cytokines by cells of IVD components such as the NP, the AF, and various cells of the immune sys- Correspondence: Mohamad Bydon, Department of Neurologic Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel.: +1.507.284.3331 - Fax: +1.507.284.5206. E-mail: bydon.mohamad@mayo.edu Key words: intervertebral disc degeneration; protein; mRNA; pro- teomics; human studies; literature review. Contributions: JZ, data collecting and analyzing; all authors, manu- script reviewing. Conflict of interest: the authors declare no potential conflict of interest. Received for publication: 27 April 2017. Accepted for publication: 6 June 2017. ©Copyright J. Zhang et al., 2017 Licensee PAGEPress, Italy Journal of the American Academy of Regenerative Medicine 2017; 1:7203 doi:10.4081/jaarm.2017.7203 This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. [page 2] [Journal of the American Academy of Regenerative Medicine 2017; 1:7203] Molecular factors in intervertebral disc degeneration Jessie Zhang, 1,2 Victor M. Lu, 1,2 Andre J. van Wijnen, 3 Panagiotis Kerezoudis, 1,4 Isobel Yeap, 1,2 Lin Cong, 3 Noelle Larson, 3 Wenchun Qu, 5 Ahmad Nassr, 3 Mohamad Bydon 1,4 1 Mayo Clinic Neuro-Informatics Laboratory, Mayo Clinic, Rochester, MN, USA; 2 Sydney Medical School, University of Sydney, Australia; Departments of 3 Orthopedic Surgery, 4 Neurologic Surgery, 5 Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN, USA Non-commercial use only