Intra-articular hyaluronan injections for the treatment of osteoarthritis: perspective for the mechanism of action

Osteoarthritis (OA) is one of the leading causes of global disability, with a tremendous individual and socioeconomic burden. ¹ Interest in minimally invasive methods, such as injection therapies, that may prevent or reverse the progression of cartilage disease, mostly for the treatment of early stages of OA, has grown, including the use of hyaluronic acid or hyaluronan (HA), platelet-rich plasma (PRP) and cell-based therapies.^2–4 Among these approaches, intra-articular injections of HA have been one of the most frequently performed therapies. While there is an extensive body of evidence surrounding the use of HA injections, especially for the treatment of knee OA, this is composed of heterogeneous trials with conflicting conclusions. ⁵ Even though the vast majority of the available literature covers the potential clinical effect of HA injections, considerable controversy still persists regarding its clinical effectiveness. Over several decades there have been multiple attempts to determine the ideal molecular weight and concentration of HA that would deliver the best clinical outcome, without considerable consensus. Due to the disagreement, inconsistent data and remaining debate, although HA injections may denote a safe alternative that could offer temporary reduction in pain for certain patients with knee OA, the current evidence base could not advocate its use.^6,7 In this sense, it is critical to acknowledge that not all intra-articular HA products should be treated as a single group, since, for example, products with a molecular weight >3000 kDa and products derived from biological fermentation have been related to superior efficacy and safety. ⁸

Significant efforts have been undertaken to reveal pharmacologic activity of HA, however, little is known about the underlying specific biochemical interactions through which HA acts. The observation that HA concentration and molecular mass are both decreased in joints with OA, resulting in decreased viscosity of the synovial fluid, led to the development of HA injections as a synovial fluid enhancement therapy termed ‘visco-supplementation’.^9,10 This effect, which was thought to increase joint lubrication by restoring or supplementing synovial fluid viscoelasticity, was one of the earliest mechanisms suggested. Nonetheless, the visco-supplementation may only substantiate this effect during the first day or two after injection, as this exogenously applied HA is rapidly cleared from OA synovial fluid (<24 h), and degraded during transport through the lymphatics into circulation and into liver hepatocytes for final degradation. ¹¹ This short time frame is inconsistent with the apparent reported pain relief of several weeks or months following a single or sequential HA injections. Therefore, if intra-articular HA is to have a positive effect, other than placebo effect, it must be due to one of the other proposed mechanisms of action, including potential anti-inflammatory, analgesic or chondroprotective properties (increased collagen synthesis and prevention of chondrocyte apoptosis).^11,12 Yet the clinical effectiveness of HA, which is at best modest and persists beyond the intra-articular residence of the HA, is still a matter of ongoing research, and the related mechanism of action is still to be defined.

A new perspective to investigate the effect of intra-articular HA injections into the osteoarthritic joint has emerged with a better understanding of the ubiquitous presence of hyaluronan matrices, both in normal pericellular matrices surrounding most cells and in pathological biological processes. ¹³ HA has been recognized to have a key role in regulating inflammation. During inflammation, the accumulation and turnover of HA matrices by multiple cell types has been documented. ¹³ Furthermore, HA and its binding proteins can regulate the expression of inflammatory genes, the release of inflammatory cytokines, and the recruitment of inflammatory cells, thereby modulating inflammation and mediating tissue damage. ¹⁴ Modified HA extracellular matrices have been associated with the severity of inflammation in diverse diseases, including asthma and inflammatory bowel disease. During many inflammatory processes, HA becomes covalently modified with heavy chain (HC) proteins transferred by TNFα-stimulated gene 6 (TSG6) from inter-α-inhibitor (IαI) to form HC–HA matrices, which increases its avidity for leukocytes and other inflammatory cells. ¹⁵ Intra-articular injections of exogenous HA, then, may influence this reaction or interact with these anomalous HC–HA matrices, thereby facilitating the reestablishment of joint homeostasis. The inflammatory process in the synovial fluid of osteoarthritic joints might involve fragmentation of native HA and transfer of HC from serum exudate IαI onto HA by the enzyme TSG6. This TSG6 enzyme is capable of redistributing HC onto HA in a two-way reversible path. Consequently, the injection of a large amount of exogenous HA, typically 3–6 times the amount present in the synovial fluid, potentially aids the enzyme TSG6 to remove a large proportion of the HC from the synovial fluid HC–HA matrix. This would lower overall amounts of synovial HC–HA when the large amount of exogenous HC–HA is removed to restore the normal level of the synovial HA concentration within a day or two. This exogenous HA dose diminishment of synovial HC–HA levels, then, could reduce the inflammatory state providing a possible mechanism of action to explore and optimize.

Remarkably, then, biology uses the synthesis of HA and its HC modification as a tactic to respond to different forms of stress by forming abnormal monocyte-adhesive HC–HA matrices. In line with these findings, an increased understanding of the central role that HA might have in the pathogenesis of the disease we are treating (i.e. OA) is needed. New approaches to treat OA at different stages of progression, or optimization of current approaches using intra-articular HA injection, should be conceived after determining the basic mechanisms of inflammation, extracellular matrix dynamics and the interaction between resident cells regulated by HA as it relates to OA progression.^16,17 Furthermore, in order to establish the clinical efficacy of HA injections it will be imperative to continue to develop and optimize formulations of HA, and to analyze the evidence in light of the intrinsic differences between HA products.