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Voltage-Dependent Calcium Channels in Chondrocytes: Roles in Health and Disease

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Voltage-Dependent Calcium Channels in Chondrocytes: Roles in Health and Disease Curr Rheumatol Rep (2015) 17: 43 DOI 10.1007/s11926-015-0521-4 OSTEOARTHRITIS (MB GOLDRING, SECTION EDITOR) Voltage-Dependent Calcium Channels in Chondrocytes: Roles in Health and Disease Csaba Matta1,2 & Róza Zákány 2 & Ali Mobasheri1,3,4 Published online: 17 May 2015 # Springer Science+Business Media New York 2015 Abstract Chondrocytes, the single cell type in adult articular and maturation. We also highlight the fact that activation of cartilage, have conventionally been considered to be non- VDCC function appears to accompany various inflammatory excitable cells. However, recent evidence suggests that their aspects of osteoarthritis (OA) and, based on in vitro data, the resting membrane potential (RMP) is less negative than that of application of nifedipine and/or verapamil may be a promising excitable cells, and they are fully equipped with channels that approach for ameliorating OA severity. However, very few control ion, water and osmolyte movement across the chon- studies on clinical outcomes are available regarding the influ- drocyte membrane. Amongst calcium-specific ion channels, ence of calcium antagonists, which are used primarily for members of the voltage-dependent calcium channel (VDCC) treating cardiovascular conditions in OA patients. This review family are expressed in chondrocytes where they are function- is intended to stimulate further research on the chondrocyte ally active. L-type VDCC inhibitors such as nifedipine and ‘channelome’, contribute to the development of novel thera- verapamil have contributed to our understanding of the roles peutic strategies and facilitate the retargeting and reposi- of these ion channels in chondrogenesis, chondrocyte signal- tioning of existing pharmacological agents currently used for ling and mechanotransduction. In this narrative review, we other comorbidities for the treatment of OA. discuss published data indicating that VDCC function is vital for chondrocyte health, especially in regulating proliferation Keywords Osteoarthritis (OA) . Joint inflammation . Cartilage . Chondrocyte . Voltage-dependent calcium channel . Calcium channel blockers . Nifedipine . Verapamil This article is part of the Topical Collection on Osteoarthritis * Csaba Matta [email protected] Introduction A thin layer of hyaline cartilage covers the articulating bones 1 The D-BOARD European Consortium for Biomarker Discovery, Department of Veterinary Preclinical Sciences, School of Veterinary in most load-bearing synovial joints in the human body, Medicine, Faculty of Health and Medical Sciences, University of where it enables frictionless movement and provides protec- Surrey, Guildford, Surrey GU2 7XH, UK tion for subchondral bone. Adult cartilage contains a single 2 Department of Anatomy, Histology and Embryology, Faculty of cell type, the chondrocyte, with the main function of main- Medicine, University of Debrecen, Nagyerdei krt. 98, taining the proper composition of the extracellular matrix Debrecen H-4032, Hungary (ECM), in which they are embedded. The ECM of hyaline 3 Arthritis Research UK Centre for Sport, Exercise and Osteoarthritis, cartilage primarily consists of a dense and cross-linked mesh- Arthritis Research UK Pain Centre, Medical Research Council and work of fibrillar collagens (predominantly type II collagen) Arthritis Research UK Centre for Musculoskeletal Ageing Research, University of Nottingham, Queen’s Medical Centre, and other minor collagens (mainly type VI, IX and XI) that Nottingham NG7 2UH, UK are incorporated in the fibrillar collagen network, regulating 4 Center of Excellence in Genomic Medicine Research (CEGMR), fibril assembly, organisation and degradation. This matrix is King Fahd Medical Research Center (KFMRC), King AbdulAziz packed with large aggregating proteoglycans (e.g. aggrecan) University, Jeddah 21589, Kingdom of Saudi Arabia and their constituent glycosaminoglycans (GAGs; e.g. 43 Page 2 of 11 Curr Rheumatol Rep (2015) 17: 43 chondroitin sulphate, keratan sulphate, hyaluronan, etc.), features of VDCCs are largely conserved, their physiological which possess a net negative charge attracting counteracting and pharmacological properties can be very different. The α1 cations and high quantities of osmotically obliged water subunit, besides forming the pore, also determines the type of (approx. 70 % of the net weight of ECM) [1]. Small the channel; to date, 10 different α1 subunits have been iso- leucine-rich proteoglycans (SLRPs) such as decorin, biglycan lated, which can be classified into the structurally and func- and fibromodulin are specialised ECM molecules that contain tionally related families of CaV1, CaV2andCaV3 (see Table 1). multiple repeats of a leucine-rich structural motif, flanked by The other ancillary subunits (four α2δ,fourβ and eight dif- cysteine residues. SLRPs also modify the deposition and ar- ferent γ subunits are known) modulate the functional proper- rangement of fibrillar collagen fibres in the ECM. They also ties of these ion channels. There are five different types of interact with cells and soluble growth factors such as VDCCs; members of the L-type (or ‘long lasting’)groupof 2+ transforming growth factor β (TGF-β) that may affect the Ca channels contain one of the CaV1.1, CaV1.2, CaV1.3 or proliferation of chondrocytes in addition to modifying the CaV1.4 α1 subunits; the N-type (‘neural’)containsCaV2.1; composition of the ECM. the P/Q-type (‘Purkinje’)containsCaV2.2; the R-type (‘resid- As a unique type of connective tissue, mature articular ual’)containsCaV2.3; and members of the T-type (‘transient’) cartilage is avascular, aneural and alymphatic [2]. group contain CaV3.1, CaV3.2 or CaV3.3 α1 subunits Chondrocytes are surrounded by a pericellular matrix and (Table 1)[14•, 15]. It is of note that the L, N, P/Q and R- are situated in cavities called lacunae within the ECM, where type calcium channels are activated at high voltage (HVA), they exist in a hypoxic microenvironment [3, 4] and control whilst T-type calcium channels are activated at negative rest- ECM turnover and homeostasis in response to mechanical ing membrane potential (RMP) values and are considered as loading [5] despite having a rather slow (mainly anaerobic) members of the low-voltage-activated (LVA) family [16]. metabolism. Due to the fact that chondrocytes reside within Inhibitors such as nifedipine or small peptide toxins from the peculiar milieu of the ECM (which is acidic, hypertonic certain spider, snail or scorpion species have contributed to and hyperosmotic [6–8]), and since their function and differ- our understanding of the roles of these calcium channels in entiation is strongly dependent on intracellular calcium ho- various models. VDCCs are targets of existing drugs for the meostasis [9, 10], they deploy a whole range of ion channels treatment of various cardiovascular diseases and central ner- to enable ion transport across the plasma membrane; the col- vous system disorders. Dihydropyridines, phenyl- lection of ion channels is referred to as the chondrocyte alkylamines, benzodiazepines and other small molecules are ‘channelome’ [11]. Albeit generally considered to be non- widely used potent L-type channel blockers. Nifedipine is a excitable cells, chondrocytes and chondroprogenitor cells member of the dihydropyridine family of calcium channel have been reported to express various voltage-dependent po- blocking agents. Its mechanism of action is to inhibit calcium tassium channels (KV), ATP dependent potassium channels influx, thereby causing, for example, smooth muscle cell re- (KATP), large and small conductance calcium-activated potas- laxation and consequent vasodilation. Therefore, nifedipine, sium channels (BK and SK), transient receptor potential chan- along with other dihydropyridines such as amlodipine or nels (primarily TRPV1 and TRPV4), purinergic receptors nicardipine, is a potent and widely used antihypertensive drug (both P2X and P2Y subfamily members), voltage-gated and [17]. The phenyl-alkylamine verapamil, another potent calci- epithelial sodium channels, chloride channels and also um antagonist, binds to a distinct site on the ion channel and is voltage-dependent calcium channels (VDCCs) [11–13]. also widely used as an antihypertensive drug [18]. The L-type channels are sensitive to the neurotoxin calciseptine, in addi- tion to the conventional blockers [16]. The main modulators Physiology and Pharmacology of Voltage-Dependent of N-type calcium channels are ω-conotoxins; P/Q-type chan- Calcium Channels nels are selectively blocked by ω-agatoxins; and the peptide neurotoxin SNX-482 is a selective R-type calcium channel Under physiological conditions, Ca2+ concentration is several inhibitor. To date, no specific blockers for T-type Ca2+ chan- thousand times higher in the extracellular space than in the nels have been identified [19]. cytoplasm. Activation of VDCCs results in rapid elevation of intracellular Ca2+ levels and initiates various cellular re- sponses. VDCCs are typically closed at resting membrane VDCCs and the Effects of Nifedipine/Verapamil potentials, and their opening requires depolarization. VDCCs, on Chondrocytes along with other structurally similar voltage-gated ion chan- nels such as NaV or KV channels, are tetrameric cation chan- Whilst the roles of VDCCs in excitable cells such as muscle, nels with four transmembrane domains (I–IV) surrounding a nerve or endocrine cells are well established, they act in an selective central pore and typically consist of α1, α2δ, β and γ even more complex way in non-excitable
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