Symptomatic versus Asymptomatic Intervertebral Disc Degeneration: Is Inflammation the Key?

Degenerated intervertebral discs (d-IVDs) contribute to low back pain (LBP) and are highly common. While some d-IVDs cause discogenic LBP, others are pain-free. Understanding the differences in pathophysiology between painful and pain-free intervertebral disc degeneration (IDD), especially the pathogenic signaling involved in the regulation of painful d-IVDs, is vital for achieving satisfactory effects in clinical treatment. In this review, we revisit recent findings on the detection of inflammatory factors in d-IVDs and summarize the differences between d-IVDs that are painful and those that are pain-free. We postulate that persistent inflammation and innervation are the key factors distinguishing those that are symptomatic and those that are not. This highlights the necessity to use painful, rather than pain-free, degenerated discs in the mechanistic study of disc degeneration and in the development of regenerative approaches, to avoid false positive/negative outcomes. Based on previous molecular d-IVD studies, we also postulate the signaling events from disc overload/ injury to discogenic pain. Although these proposed events are supported by experimental findings, many details about how they are interconnected are not addressed and therefore require experimental investigation.