The chondrocyte channelome: A narrative review

Abstract

Chondrocytes are the main cells in the extracellular matrix (ECM) of articular cartilage and possess a highly differentiated phenotype that is the hallmark of the unique physiological functions of this specialised load-bearing connective tissue. The plasma membrane of articular chondrocytes contains a rich and diverse complement of membrane proteins, known as the membranome, which defines the cell surface phenotype of the cells. The membranome is a key target of pharmacological agents and is important for chondrocyte function. It includes channels, transporters, enzymes, receptors, and anchors for intracellular, cytoskeletal and ECM proteins and other macromolecular complexes. The chondrocyte channelome is a sub-compartment of the membranome and includes a complete set of ion channels and porins expressed in these cells. Many of these are multi-functional proteins with "moonlighting" roles, serving as channels, receptors and signalling components of larger molecular assemblies. The aim of this review is to summarise our current knowledge of the fundamental aspects of the chondrocyte channelome, discuss its relevance to cartilage biology and highlight its possible role in the pathogenesis of osteoarthritis (OA). Excessive and inappropriate mechanical loads, an inflammatory micro-environment, alternative splicing of channel components or accumulation of basic calcium phosphate crystals can result in an altered chondrocyte channelome impairing its function. Alterations in Ca signalling may lead to defective synthesis of ECM macromolecules and aggravated catabolic responses in chondrocytes, which is an important and relatively unexplored aspect of the complex and poorly understood mechanism of OA development.

Prevention of Injury-Induced Osteoarthritis in Rodent Temporomandibular Joint by Targeting Chondrocyte CaSR

“…Many Ca 2þ channels have been reported to potentially mediate the stress-induced ER Ca 2þ loading in chondrocytes. (41) T-type Ca 2þ channel and TRPV channel (36) are the most potential candidates and could represent other pharmaceutical targets for OA prevention and treatment. In keratinocytes, CaSRs are co-localized with PLC-1 ATP-Ca 2þ transporter and IP 3 -receptor in Golgi apparatus.…”

Physiological Effects of the Electrogenic Current Generated by the Na /K Pump in Mammalian Articular Chondrocytes

“…skin or muscle 10,67 . These differences and the resulting changes in Na + /K + pump activity and baseline chondrocyte conductances were a focus of our previous paper 38 and have been studied previously in physiological and pathophysiological settings 10,14,16,43,44 . These considerations, when combined with the demonstration that the healthy bovine and human chondrocytes expresses a number of different isoforms of the a, b, and g subunits of the Na + /K + pump protein complex 39,41 , raise important questions concerning the relative sizes of the electrogenic current and related changes in membrane potential that would be expected due to predominant expression of speci c combinations of the a, b, and g subunits 42,45 .…”

“…The presence of mature healthy chondrocytes, and a full functional repertoire for these cells are essential for normal articular joint motion. Some of the important classes of transducer elements at the level of individual chondrocytes are ion channels, exchangers or pumps that are expressed in the surface membrane [10][11][12][13][14][15][16] . The signi cance of these integral membrane proteins, functioning individually or in concert, was rst recognized with respect to the ability of chondrocytes to quickly and accurately volume regulate in response to even small changes in osmotic strength of the surrounding synovial uid 17,18 .…”

“…Within the last decade, a number of different ion selective channels and exchangers have been identi ed and shown to play essential roles in chondrocyte physiology 16,[19][20][21][22][23][24] . Any such ion channel being functional in chondrocytes may seem somewhat surprising to researchers working on excitable cells, since the chondrocyte is considered to be a non-excitable cell.…”

“…Any such ion channel being functional in chondrocytes may seem somewhat surprising to researchers working on excitable cells, since the chondrocyte is considered to be a non-excitable cell. However, despite chondrocytes being nonexcitable cells, their dynamic membrane potential serves many cellular roles 25 , are metabolically active 16 , especially during hypertrophy 26 and are capable of responses to commonly used drugs for treating hypertension 27 . Metabolic activity occurs at lower levels, especially in fully differentiated and senescent chondrocytes 28,29 .…”