Osteoarthritis (OAS) is characterized by cartilage degeneration with the loss of the extracellular matrix that allows the joint to compress without damage. The chondrocytes in OAS show multiple alterations in their metabolism. These occur as part of the chondrocyte response to both external mechanical and internal biochemical stimuli. Chondrocytes also produce multiple inflammatory and enzymatic proteins that cause the cartilage to breakdown in OAS. Despite this level of understanding of the pathogenesis of OAS, little is known about how to arrest or modulate the course of the disease and how it operates at the molecular level. Ion channels in chondrocytes are diverse and required for multiple processes that contribute to their physiological role. Thus, in OAS, these channels are expressed at altered levels. In contrast, when mechanosensory ion channels are deleted from cartilage cells, age-related OAS rates are reduced.
Pain is a significant marker of OAS, mostly due to the signals generated by peripheral sensory neurons found in abundance in joint synovium and subchondral bone. These are known to have voltage-gated sodium channels (VGSCs) in unique arrays, represented as Nav1.1-1.9. VGSCs are mostly found on excitable cells like neurons but also on glial cells, macrophages, and malignant cells. The pain in OA may be due to the ingrowth of new blood vessels and sensory nerve rootlets into the joint tissue. Some research has indicated that chondrocytes, or cartilage cells, have VGSCs, but not much is known about their function or regulation or how they contribute to OA symptoms and progression. Their expression is encoded via genes SCN1A-SCN11A. Among these, Nav1.7-1.9 are found mostly in the peripheral sensory neurons, within the sensory nerve collections near the spinal cord, or dorsal root ganglia .
They are involved in generating and transmitting pain impulses within peripheral pathways. Prior research traced a sodium current within chondrocytes, which has now been shown to be caused in great part by Nav1.7. These channels regulate chondrocyte metabolism via secreted molecule profile. While Nav1.7 on chondrocytes plays a key role in chondrocytes biology, leading to the destruction of cartilage and pain in OAS, these channels on the DRG neurons are involved in pain sensations in OAS itself. Nav1.7 blockade could help chondrocytes regulate their anabolic and catabolic activity in coordination with the local environment, whether or not they express these ion channels. This indicates their paracrine as well as autocrine role. Moreover, when the expression of Nav1.8 on the DRG is reduced, pain associated with OAS decreases.
Additionally, Nav1.7 has been indicated to be key to pain signaling, making it a potential target for therapeutic pain relief. And this seems the case: researchers found that functional Nav1.7 channels were expressed on human cartilage cells in OAS, being responsible for over 60% of sodium ion flux within these cells. The same channels were also expressed on DRG neurons. In mouse models, they found that when the expression of these channels at the level of the DRG was suppressed by genetic deletion, OAS-associated pain was reduced, but disease progression continued. Conversely, the expression of Nav1.7 in OAS chondrocytes was found to be a regulator of progression. The inhibition of their expression in these cells increased anabolic pathways and reduced catabolism. In mice, this resulted in improved OAS checkable features.
There was decreased formation of bone spurs, less cartilage loss, decreased thickening of subchondral bone, and reduced pain and synovial inflammation. When sodium channels were blocked, either selectively or altogether, by pharmacological agents, the resulting blockade of Nav1.7 led to significantly reduced joint damage and preserved joint structure. Similarly, the animals showed fewer behavioral symptoms of pain related to OAS. In general, Nav1.7 blockade prevents cartilage cell destruction within an inflammatory environment but allows normal anabolic pathways to proceed. This finding was established in animal models as well as on primary human chondrocytes from OAS patients. . Importantly, carbamazepine, a drug in common clinical use with FDA approval, is effective in Nav1.7 blockade.
Deeper exploration showed that Nav1.7 blockade modulates calcium ion signaling pathways within the chondrocytes. Calcium in cell cytosol may become dangerous bacause of its ability to activate portein kinase cascades (PKCs, CAMKs) and proteolytic enzymes (calpains), which are responsible to the breakdown of cellular structures. This, in turn, leads to altered secretion of proteins and other biologically active molecules by the chondrocytes, like HSP (heat shock protein) 70, which is protective against cellular stress. Calcium signaling, moreover, may associate to cellular acidification by activation of sodium-proton exchangers (e.g. NHE-1) and activation of stress signaling pathways (e.g. p38 stress kinase) that induce cells to synthesize inflammatory cytokines. These are notoriously responsible for the painful inflammatory symptoms in OAS.
These findings add to previous studies suggesting a crucial role for VGSCs in non-excitable cells (non neural or heart-derived). The effectiveness of carbamazepine in preventing cartilage destruction in animal models of OA suggests that it could be repurposed for OA treatment in humans, pending further validation. The implication for this repurposing in not indifferent, since OAS is an extremely alarming medical condition which affects more tha 20 million people just in USA, making it a serious burden of public health. Either carbamazepine repurposing or the discovery of a more selective VGSCs inhibitors are auspicable, in the “name of pain”.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
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