Pathophysiology of Hyaluronan Accumulation/Depolymerization in Osteoarthritic Joints

Abstract

In healthy articular cartilage, the extracellular matrix (ECM) is properly maintained by the overall anabolic and catabolic balance of slow synthesis and degradation, a so-called homeostatic state, under the influence of synovial metabolism. Though the ECM of articular cartilage tissue contains low amounts of hyaluronan (HA), its main components are collagen, type II, IX, and XI, and proteoglycans, such as aggrecan. Nevertheless, HA plays crucial roles in cartilage, especially in retaining aggrecan in tissues. 1 Previous studies on ECM degradation in osteoarthritis (OA) focused on the degradation of the proteoglycan, aggrecan, 2 but not that of HA. The mechanism of HA synthesis in articular cartilage and synovium has been elucidated by the expression and functional analysis of hyaluronan synthase 1 to 3. However, research on the HA degradation system has not progressed because the main enzymes involved are not well understood. The research article by Momoeda et al, 3 in this issue of The American Journal of Pathology, provides new findings on the involvement of a novel hyaluronidase in OA development using genetically manipulated mice.Among the molecules in the hyaluronan-degrading enzyme (HYAL) family, HYAL1 and HYAL2 are widely expressed and have been hypothesized to be the major hyaluronidases involved in HA catabolism in somatic tissues. However, research data on HYAL1 and HYAL2 do not support them being the central hyaluronidases that cleave high-molecularweight (HMW) HA on the cell surface or extracellular space. This is because both HYAL1 and HYAL2 have enzymatic activity in the acidic condition, 4,5 whereas HYAL2, which has enzymatic activity on the cell membrane, has 50 times lower enzymatic activity than HYAL1. 6 Recently, two new molecules with strong hyaluronan degrading activity have been identified. First, KIAA1199, a deafness gene of unknown function, was reported to play a central role in HA degradation in the dermis of healthy skin

Expression and regulation of recently discovered hyaluronidases, HYBID and TMEM2, in chondrocytes from knee osteoarthritic cartilage

“…Differential roles of HYBID and TMEM2 in normal and OA cartilage remain to be clarified. However, our recent study on the experimental knee OA models using Hybid-deficient mice demonstrated that cartilage destruction and osteophyte formation are suppressed in Hybid-deficient mice and suggested that Hybid plays a key role in the progression of mechanically induced knee OA by HA degradation in joint tissues including the articular cartilage and synovium 22 , and could be a potential therapeutic target on the onset of OA 23 . In addition, a very recent study by Deroyer et al reported that HYBID (CEMIP, KIAA1199) overexpressed by OA synovial tissue is implicated for synovial inflammation and hyperplasia 24 .…”