Detrimental Role for Human High Temperature Requirement Serine Protease A1 (HTRA1) in the Pathogenesis of Intervertebral Disc (IVD) Degeneration

Abstract

Background: HTRA1 has been associated with intervertebral disc (IVD) degeneration although its role is unknown. Results: HTRA1 up-regulated matrix metalloproteinase (MMP) production by IVD cells via the generation of fibronectin fragments. Conclusion: HTRA1 plays a detrimental role in the pathogenesis of IVD degeneration. Significance: HTRA1 may represent a novel therapeutic target for the treatment of spinal disc degeneration.

Chondroadherin Fragmentation Mediated by the Protease HTRA1 Distinguishes Human Intervertebral Disc Degeneration from Normal Aging

“…Two forms of HTRA1 have been described: the larger corresponds in size to the intact protein, and the smaller is suggested to represent a proteolytically processed form of HTRA1 (41). The intact form has been reported to be present in all human discs, whereas the processed form is more abundant in degenerate discs (25). This has been confirmed by our study of the HTRA1 protein as a ϳ50-kDa protein representing the intact form is present in all samples, and a ϳ42-kDa protein representing the processed form is more abundant only in the degenerate samples.…”

“…Mounting evidence suggests that it plays a central role in the pathology of arthritic diseases, such as osteoarthritis (22,23), and in the degradation of articular cartilage (24). Elevated levels of HTRA1 have also been found in degenerate IVD tissue (25). Other members of the HTRA family have not yet been described in the disc (21).…”

Decrease in serine protease HtrA1 expression correlates with grade and recurrence in meningiomas

“…HtrA1 gene was initially identified as being expressed in normal human fibroblasts, but not after their transformation with simian virus 40 (SV 40) [2]. Since then while the physiological function of human HtrA1 remains largely unclear, it was shown to be involved in the pathogenesis of various diseases such as osteoarthritis, preeclampsia or CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy) [3][4][5]. Currently alterations of these proteins associated with specific tumor behaviour are receiving increasing attention.…”

Nerve Growth Factor Is Regulated by Toll-Like Receptor 2 in Human Intervertebral Discs

“…The causes of disc degeneration are multifaceted and not well understood, yet genetics, mechanical load, or traumatic injury to the disc along with several life style choices are known to contribute to the etiologies of disc degeneration (1). During degeneration there is a large increase in catabolic proteases including matrix metalloproteinases (2,3), cathepsins (4,5), high temperature requirement serine protease A1 (HTRA1) (6,7), and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) (8,9). Protease activity degrades the extracellular matrix (ECM), and the generated ECM fragments can potentially function as endogenous danger-associated patterns (DAMPs) also known as "alarmins" (10).…”