Osteoarthritis (OA) is among the most widespread of joint conditions, and there is no effective preventive strategy currently. It is caused by the breakdown of joint cartilage, causing pain and inflammation of the joint and eventually causing crippling limitation of mobility.
Recently, a new study in Nature described Nav1.7 as a key regulatory molecule in cartilage cells and reported the effectiveness of Nav1.7 blockade in reducing pain and slowing progression in OA.
Introduction
OA is characterized by cartilage degeneration with the loss of the extracellular matrix that allows the joint to compress without damage. The chondrocytes in OA 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 degenerative molecules that cause the cartilage to break down in OA. Despite this level of understanding of the pathogenesis of OA, 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 OA, these channels are expressed at altered levels. In contrast, when mechanosensory ion channels are deleted from cartilage cells, age-related OA rates are reduced.
Pain is a significant marker of OA, 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, called dorsal root ganglia (DRG). They are involved in generating and transmitting pain impulses within peripheral pathways.
Moreover, when the expression of Nav1.8 on the DRG is reduced, pain associated with OA decreases. Additionally, Nav1.7 has been indicated to be key to pain signaling, and genetic and pharmacologic manipulation confirm this role, making it a potential target for therapeutic pain relief.
The current study focused on RNA-sequencing analysis to explore whether Nav1.7 expressed on chondrocytes was involved in OA-related changes.
What did the study show?
The results show that Nav1.7 is a VGSC expressed in the cartilage cells and in DRG neurons in patients with OA.
The researchers found that functional Nav1.7 channels were expressed on human cartilage cells in OA at a density of 0.1 to 0.15 channels per μm2 and 350 to 525 channels per cell. They are responsible for over 60% of sodium ion flux within these cells in OA. 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, OA-associated pain was reduced, but OA progression continued unabated.
Conversely, the expression of Nav1.7 in OA chondrocytes was found to be a regulator of OA progression. The inhibition of their expression in these cells increased anabolic pathways and reduced catabolic activity.
In mice, this resulted in improved OA features. There was decreased formation of bone spurs or osteophytes, less cartilage loss, decreased thickening of subchondral bone, and reduced pain and synovial inflammation compared to mice with intact Nav1.7 expression.
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 OA.
Importantly, carbamazepine, a drug in common clinical use with FDA approval, is effective in Nav1.7 blockade.
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 OA patients.
Deeper exploration showed that Nav1.7 blockade modulates calcium ion signaling pathways within the chondrocytes. This, in turn, leads to altered secretion of proteins and other biologically active molecules, like HSP (heat shock protein) 70 and midkine, by the chondrocytes. The result is improved cartilage quality and reduced destruction, slowing OA progression and relieving pain.
What are the implications?
“Identification of Nav1.7 as a novel chondrocyte-expressed, OA-associated channel uncovers a dual target for the development of disease-modifying and non-opioid pain relief treatment for OA.”
These findings add to previous studies suggesting a crucial role for VGSCs in non-excitable cells, where they are involved in a number of functions associated with the cell’s intrinsic function and activity. These include phagocytosis, cell motility, and the release of cytokines.
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 OA, these channels on the DRG neurons are involved in pain sensations in OA.
Nav1.7 blockade could help chondrocytes regulate their anabolic and catabolic activity in coordination with the local environment, whether or not they express these VGSCs. This indicates their paracrine as well as autocrine role. 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.
