Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 2018 Apr 22;176(10):1412–1420. doi: 10.1111/bph.14204

Joint problems arising from lack of repair mechanisms: can cannabinoids help?

Natalia Malek 1, Katarzyna Starowicz 2,✉
PMCID: PMC6487548  PMID: 29574720

Abstract

Osteoarthritis (OA) is the most common disease of joints, which are complex organs where cartilage, bone and synovium cooperate to allow a range of movements. During progression of the disease, the function of all three main components is jeopardized. Nevertheless, the involvement of each tissue in OA development is still not established and is the topic of the present review. The OA therapies available are symptomatic, largely targeting pain management rather than disease progression. The strong need to develop a treatment for cartilage degeneration, bone deformation and synovial inflammation has led to research on the involvement of the endocannabinoid system in the development of OA. The current review discusses the research on this topic to date and notes the advantages of exploiting endocannabinoid system modulation for cartilage, bone and synovium homeostasis, which could prevent the further progression of OA.

Linked Articles

This article is part of a themed section on 8th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc

Abbreviations

2‐AG

2‐aracydonylglycerol

AEA

anandamide

CB1 receptor

cannabinoid receptor 1

CBD

cannabidiol

CCL2

chemokine (C‐C motif) ligand 2

FAAH

fatty acid amide hydrolase

FLS

fibroblast‐like synoviocyte

GPR18/55

GPCR18/55

OA

osteoarthritis

RA

rheumatoid arthritis

RANK

receptor activator for NFκB

RANKL

RANK ligand

TRPV1

transient receptor potential vanilloid 1

Introduction

Osteoarthritis (OA) is the most common type of arthritis, and is a painful degenerative joint disease. It usually affects larger joints that are responsible for weight bearing and is thus one of the main causes of motor disability worldwide. The occurrence of OA increases with age and is more common in women than in men (Aigner et al., 2004). The joint is an organ constituted mainly of cartilage, synovial fibroblasts and bone tissue, and although OA was traditionally thought to be a cartilage‐based disease, it is now known that during its development, all three components (cartilage, subchondral bone and synovial fibroblasts) may be affected and can contribute to disease progression. OA was previously classified as a non‐inflammatory type of arthritis. Nevertheless, recent reports indicate that some inflammation occurs and that pro‐inflammatory cytokines are released into the joint (Robinson et al., 2016). Furthermore, a group of OA patients has reported neuropathic pain‐like symptoms, which may be a result of damage to the nerves underlying cartilage in the joint (Sofat and Kuttapitiya, 2014). OA has a complex origin and various phenotypes, so we would like to discuss the involvement of cartilage, subchondral bone and synovium in the context of OA.

Most of the currently used treatment paradigms in OA are focused on alleviating pain, which should counteract the reduction in a patient's mobility (Sarzi‐Puttini et al., 2005). Nonsteroidal anti‐inflammatory drugs, which are often administered to OA patients, can lead to adverse reactions of the gastrointestinal system. Intraarticular injections of corticosteroids may only temporarily alleviate joint pain, and intraarticular injections of hyaluronic acid only benefit some patients, and the effect wears off over time (Priano, 2017).

The development of disease‐modifying drugs for OA is still in the primary phase. Cytokines are treatment targets, and their inhibition could reduce the inflammatory component of OA (Lubberts et al., 1998; McDougall et al., 2017 ; Wei et al., 2017). Inhibitors of metalloproteinases, which degrade the extracellular matrix, have shown potential in preclinical studies, but clinical trials in humans were unsatisfactory (Milner and Cawston, 2005). The lack of success in disease‐modifying therapies of OA may lie in the timing of the intervention and poor regeneration abilities of joint tissues. Perhaps the highest potential is in preventing the disease onset and treatment at early stages rather than after severe pain symptoms occur.

One promising target for OA‐focused therapy is the endocannabinoid system. Cannabinoids are a family of lipid mediators that act through the GPCRs: CB1 and CB2, which were originally identified as classical cannabinoid receptors (Matsuda et al., 1990 ; Munro et al., 1993) and are the main focus of this review. Several exogenous cannabinoids have been isolated from the Cannabis plant, where they occurred naturally; however, most of them are a result of chemical synthesis. Phytocannabinoids are characterized as an agonist of both cannabinoid receptors, whereas synthetic compounds have been produced to act selectively on one of the receptors. In contrast to exogenous ligands, both CB1 and CB2 receptors respond to endogenous ligands, such as anandamide (AEA) and 2‐aracydonylglycerol (2‐AG). The endocannabinoid system is a promising target in many different therapies because it is mainly switched on following injury or in the presence of a disease (Russo, 2016). Moreover, it is noteworthy that cannabinoid receptors can be manipulated directly by their ligands or indirectly by compounds that modulate levels of endocannabinoids (e.g. inhibitors of their degradation enzymes that result in the accumulation of AEA or 2‐AG). Cannabinoid ligands (in particular AEA) are known to activate other targets, such as transient receptor potential vanilloid type 1 (TRPV1), GPCR55 (GPR55) and GPR18 (GPR18).

The endocannabinoid system has been recognized as playing an important role in the contribution to OA disease progression and has gained increasing interest in recent years. Furthermore, cannabinoids have been proven to possess anti‐inflammatory properties and even reduce joint damage during OA (Dunn et al., 2014). Activation of the endocannabinoid system has been shown to modulate inflammation. The endocannabinoid system is postulated to modulate macrophage and mast cell activation, pro‐inflammatory cytokines and T‐cell proliferation and apoptosis (Robinson et al., 2016).

CB1 receptors are located mainly in the central and peripheral nervous system, while CB2 receptors are predominantly expressed by immune cells (both macrophages in the periphery and glial cells in theCNS) (Mbvundula et al., 2006). Moreover, both cannabinoid receptors have been shown to be expressed in chondrocyte cultures and human OA cartilage (Dunn et al., 2014), subchondral bone (Rossi et al., 2009 ; Whyte et al., 2012) and synovial tissue (Richardson et al., 2008). Synovial fibroblasts also express AEA and 2‐AG catabolic enzymes, suggesting the endocannabinoid system has a role in the maintenance of joint homeostasis (McPartland, 2008). Moreover, Schuelert et al. showed that CB1 and CB2 receptors are expressed on nerve ends that innervate the knee (Schuelert and McDougall, 2009). All this evidence suggests that the endocannabinoid system may play an important role in development of joint diseases associated with chronic pain as in OA.

Effects of cannabinoids on osteoarthritic cartilage

In the joint, a thin layer of articular cartilage covers the bone surfaces, providing a durable and pressure‐resistant buffer zone that prevents damage in subchondral bone. Cartilage is composed of articular chondrocytes surrounded by an extracellular matrix that contains type II collagen, which is responsible for resistance, and large sulfated proteoglycans, which have a negative charge that enables them to embed water within the tissue to adapt when weight is loaded onto the joint (Lories and Luyten, 2012).

The main feature of OA is the loss of articular cartilage and degradation of cartilage matrix, which is primarily attributed to cartilage breakdown. The fundamental role of cartilage in the progression of OA has been well established (Goldring, 2000b). However, chondrocytes isolated from OA patients are very diverse, ranging from normal (healthy) cells to those with severe changes in both morphology and metabolism, which must be considered in human tissue studies. Chondrocytes maintain cartilage homeostasis and regulate the stability between anabolic and catabolic processes (Krustev et al., 2015). Cartilage degeneration can arise from ageing, trauma, low‐grade local or systemic inflammation, metabolic syndromes, obesity and genetic predispositions (Buckwalter and Mankin, 1998). The main process contributing to this degeneration is the proteolysis of proteoglycans and collagens, which are major structural components of the cartilage matrix. Pro‐inflammatory cytokines promote the breakdown of type II collagen and proteoglycans in the cartilage, compromising the integrity of the cartilage. The breakdown of extracellular matrix surrounding the chondrocytes allows cytokines and growth factors to readily diffuse through the damaged matrix and into the cartilage more easily, resulting in breakdown and poor repair (Krustev et al., 2015). In later stages of OA, a substantial breakdown of collagen occurs, which is thought to be the point of irretrievable cartilage deprivation (Mbvundula et al., 2005). Due to the low regeneration capacity of cartilage and the lack of disease‐modifying therapy, there is a strong need to develop new therapeutic strategies that could improve chondrocyte function in OA.

There is evidence that cannabinoids have chondroprotective activity and this may aid the development of novel treatments for OA (Dunn et al., 2012). Cannabinoids have been demonstrated to have anti‐inflammatory effects and to have a positive influence, protecting against cartilage degradation in inflamed arthritic joints (Mbvundula et al., 2005 ; McDougall et al., 2008).

Chondrocytes extracted from OA‐affected joints were shown to express both CB1 and CB2 receptors even in degenerated tissues, demonstrating that these cells could respond to cannabinoids. Furthermore, studies have shown that both endocannabinoids and synthetic compounds have a direct chondroprotective effect, resulting in an inhibitory effect on proteoglycan breakdown and cartilage protection (Mbvundula et al., 2005). Thus, cannabinoids could be protective against joint degeneration in the development of OA. Cannabinoids that are designed to bind to receptors inhibiting the catabolic and pain pathways within the arthritic joint would bypass psychoactive efficacy, thus providing a novel insight into the therapy of OA (Dunn et al., 2014) (Figure 1). The CB2 receptor has been shown to regulate the susceptibility to OA in mice. Studies using the destabilized medial meniscus model of OA revealed that mice lacking CB2 receptors demonstrated more severe OA phenotype than wild‐type OA mice, and showed an increased predisposition to develop age‐related OA. Moreover, a selective CB2 agonist, HU‐308, reduced the severity of cartilage degradation in wild‐type OA mice but not in CB2‐deficient mice. In addition, pharmacological treatment with HU‐308 reduced the severity of OA changes within the whole joint. Additionally, in this study, it was found that cultured Cnr2−/− chondrocytes produce less proteoglycans in vitro than wild type chondrocytes (Sophocleous et al., 2015). Additionally, it was shown that HU‐210 and WIN55212‐2 (synthetic cannabinoids) directly prevent cartilage degradation via a CB1‐ and CB2‐dependent mechanism (Mbvundula et al., 2006 ; Dunn et al., 2014). WIN55212–2, which acts on CB2 receptors, was also found to inhibit the activity of ADAMTS‐4 (disintegrin and metalloproteinase with thrombospondin motifs 4) in articular chondrocytes treated with IL‐1β, thus preventing cartilage breakdown in OA (Dunn et al., 2014).

Figure 1.

Figure 1

Open in a new tab

Effects of CB1 and CB2 receptor ligands on joint tissue metabolism in OA. During OA, functional units of joints comprising cartilage, subchondral bone and synovium undergo uncontrolled catabolic and anabolic remodelling processes to adapt to local biochemical and biological signals. Modulation of the cannabinoid system can affect the major facets of joint biology. Cannabinoid‐based drugs aim at (i) reducing cartilage degradation and facilitating cartilage repair; (ii) causing osteoclast apoptosis and inhibit osteoclast formation in vitro, thus acting as anti‐resorption agent; and (iii) acting on syniviocytes as immunomodulatory and anti‐inflammatory agents. All those effects may be important for the treatment of OA progression. CB1 and CB2 receptor activation in OA joints could improve multiple aspects of the disease, including suppression of cartilage degradation, bone remodelling and synovitis, all of which leads to alleviation of joint destruction.

Other studies have also noted that other receptors may be responsible for the chondroprotective effect of cannabinoids. GPR55 and GPR18, which are known to respond to cannabinoid treatments, have both been shown to be expressed in normal and OA cartilage (Goldring and Marcu, 2009). Although there was no connection between GPR55 expression and cartilage degradation, the GPR18 immunopositivity of chondrocytes decreased with disease progression. This may suggest this receptor is involved in cartilage degeneration. In addition, the expression of TRPV1, which is an endogenous AEA receptor, decreased with changes occurring in chondrocytes in OA progression (Gavenis et al., 2009). These novel findings indicating the possible involvement of GPR18 and TRPV1 in cartilage metabolism could broaden the knowledge on the endocannabinoid system in OA and should be investigated further.

Although previous studies have shown that cannabinoids display chondroprotective properties, the expression of cannabinoid receptors within OA cartilage is poorly associated with the degree of degeneration. Moreover, the role of AEA in chondrocyte cell viability is still unclear. AEA has been found to decrease chondrocyte vitality, although this effect was not CB receptor‐dependent. Nevertheless, it was also shown to work in synergy with TNFα to cleave caspase‐3 and induce apoptosis, thus facilitating cartilage degeneration (Gómez et al., 2014). Therefore, it is important to further identify the role of these receptors within normal and OA cartilage to clarify their role in healthy tissue and their potential as possible targets in the treatment of OA (Dunn et al., 2016).

Subchondral bone in the pathogenesis of OA: role of cannabinoids

The widely held belief that OA is a disease of cartilage has been a subject of debate. Several investigations have led to the hypothesis that bone changes may account for joint deterioration and the development of OA. Indeed, individuals with OA exhibit striking increases in bone mass at affected sites, such as the knee and hip, and at non‐synovial sites such as the lumbar spine. Individuals with OA also have a high body mass index and exhibit an increase in bone mineral density. The latter may be the result of an abnormally high rate of metabolism of osteoblasts, which is observable in vivo and in vitro, particularly in subchondral bone (Sharma et al., 2013). An increase in bone turnover, the presence of oedema‐like lesions in subchondral bone marrow and bone attrition are strong indicators of structural deterioration of the knee in OA (Raynauld et al., 2006). Indeed, most current research highlights the fact that all of the joint components and particularly subchondral bone undergo functional and structural changes during OA progression (Funck‐Brentano and Cohen‐Solal, 2015). Given the intimate contact between the cartilage and bone, alterations of either tissue will modulate the properties and function of the other joint component. It is still a matter for debate, however, whether the subchondral bone changes occur at the same time as changes in articular cartilage, and thus are causative, or if, as a consequence of cartilage degradation, bone is intimately involved in the initiation and progression of OA, where trauma to the subchondral bone may result in cartilage degeneration (Funck‐Brentano and Cohen‐Solal, 2015). Increased trabecular bone volume with trabecular sclerosis and increased bone turnover are features of OA pathogenesis. Therefore, therapies that target bone may also be effective in OA.

There is compelling evidence suggesting the endocannabinoid system actively participates in bone cell differentiation, survival and function. The identification of both CB1 and CB2 receptors in bone mass (Idris and Ralston, 2012) suggests that pharmacological modulation of these receptors could be a valuable therapeutic approach in human bone diseases including OA (Ofek et al., 2006 ; Whyte et al., 2012). Endocannabinoids and their receptors have been reported in the skeleton, both in the bone forming cells (osteoblasts) and the bone resorbing cells (osteoclasts). The CB1 receptor is highly expressed in skeletal sympathetic nerve terminals (Tam et al., 2006). In osteoclasts, CB1 receptor are expressed at low levels, whereas CB2 receptors are present in high abundance (Ofek et al., 2006). In vivo, CB2 receptor protein is present in trabecular osteoblasts (Lian et al., 2004) and their descendants, the osteocytes, as well as in osteoclasts (Ofek et al., 2006). Osteoblasts and osteoclasts produce the endocannabinoids AEA and 2‐AG and express CB2 receptors (Idris and Ralston, 2012). Notably, studies have demonstrated abnormal bone phenotypes in mice lacking either CB1 or CB2 receptors, and these phenotypes varied with age, gender or genetic background (Idris et al., 2005). The endocannabinoid system has been implicated in maintaining bone homeostasis in a number of ways; for example, CB2 knockout mice showed accelerated age‐related osteoporosis, whereas activation of CB2 receptors increased bone formation markers (Valverde et al., 2005). The endocannabinoid system appears to regulate bone mass by signalling via peripheral CB2 receptors in both osteoblasts and osteoclasts.

There is increasing evidence to support the existence of additional cannabinoid receptors (non‐CB1 and non‐CB2) both in the CNS and the periphery, further verified in CB1 and CB2 receptor knockout mice (Valverde et al., 2005). Indeed, some actions of certain cannabinoid ligands are mediated by other receptors, TRPV1, GPR55 and GPR18. Recently, it has been reported that CB1, CB2 receptors and other receptors related to the cannabinoid system, TRPV1 and GPR55, are also involved in bone metabolism (Ofek et al., 2006 ; Whyte et al., 2012). Among the factors of importance for bone remodelling process, the molecular triad NFκB ligand (RANKL)/RANK/osteoprotegerin has emerged as an essential player not only in bone formation but also in bone resorption processes; for example, osteoblast cultures from CB1 knockout mice expressed less RANKL (cytokines for osteoclast formation), thus reducing the potential for bone resorption (Idris et al., 2009). Cell‐ and tissue‐based studies indicate that endocannabinoids influence bone remodelling by acting on CB1 and CB2 receptors expressed on bone cells.

However, because cannabinoids interact with other receptors, their potential role in the mechanism of bone remodelling needs more widespread research. Several studies have shown the presence of the classical cannabinoid receptors CB1 and CB2 and of GPR55 in bone cells, suggesting their possible role in bone remodelling processes during OA (Idris and Ralston, 2012). Indeed, the pharmacological and genetic manipulation of CB1, CB2 and GPR55 receptors can suppress bone resorption, increase bone mass and prevent bone loss. The synthetic cannabinoid AM251, a CB1 receptor antagonist/inverse agonist, and the genetic deletion of CB1 receptors have both been shown to decrease osteoblast differentiation from bone marrow‐derived cells (Idris et al., 2009). Several studies highlight the therapeutic value of CB2 receptor agonists in bone tissue formation and mineralization (Idris et al., 2008). The non‐psychoactive cannabinoid, cannabidiol (CBD), can be an effective oral anti‐arthritic therapy (Malfait et al., 2000). Moreover, CBD can reduce bone resorption, possibly by modulating GPR55 receptor signalling (Dunn et al., 2016). However, GPR55's actions are still unclear, and further research is essential to foster a deeper understanding of its role in bone metabolism, especially under pathophysiological conditions. Our recent studies demonstrate the contribution of the CB2 receptor to the cytoprotective effects of AEA on primary microglia cells in LPS‐induced neuroinflammation (Malek et al., 2015 b). We have also shown the involvement of GPR18 in these effects and suggest possible crosstalk between CB2 and GPR18 receptors (Malek et al., 2015 b). Bone remodelling has been associated with modification of sensory afferent innervation in bone cancer patients. Hence, similar mechanisms may also play a role in OA, where a possible link between the CNS and bone formation may be present. Thus, GPR18 may also be a new attractive target in bone metabolism regulation.

Last but not least, the co‐expression of TRPV1, CB1/CB2 receptors and AEA metabolic enzymes was found in both human osteoclast cultures and in native osteoclasts from human bone biopsies (Rossi et al., 2009). Moreover, agonist‐evoked calcium entry indicated that the TRPV1 receptor is functionally active in vitro. Consistently, biomolecular and functional experiments showed that resiniferatoxin, a selective TRPV1 receptor agonist, increased the expression and the activity of two specific osteoclast biomarkers, TRAP and cathepsin K. The evidence that cannabinoid and vanilloid receptors are co‐expressed in human osteoclasts suggests that they might crosstalk to modulate the intrinsic balance of bone mineralization and resorption by different actions of AEA through TRPV1 and cannabinoid receptors.

The most important feature of OA is that structural changes in the joint involve the major constituents of articulation, including subchondral bone. Whether these changes affect cartilage before reaching subchondral bone or vice versa is still a matter of debate. A resolution of this question is likely to modify what is known about this disease and any potential treatment.

Cannabinoids in synovial tissue

OA has long been considered a ‘wear and tear’ disease, implicating degeneration connected with the ageing process as its primary and sole cause. Currently, a literature review suggests that inflammation may play a pivotal role in the aetiology of OA. The discovery that many soluble mediators of inflammation, such as cytokines, actively participate in shaping the clinical situation of OA patients led to the first steps of an ‘inflammatory theory’ of the disease (Goldring, 2000a). Moreover, recent experimental data have shown that inflammatory processes may underlie the initiation and prolongation of OA, thereby opening a way to consider inflammation as a crucial factor in the disease. The classification of OA as a non‐inflammatory arthritis is an unfortunate consequence of early observations noting fewer leukocytes in OA synovial fluid compared with that of rheumatoid arthritis (RA), which is indisputably an inflammatory condition. Similarly, early studies in RA, using OA tissues and fluids as a reference, reported dramatically increased levels of inflammatory proteins in RA (Smith et al., 1997), which reinforced the notion that OA is not associated with inflammation. Moreover, in these initial studies, a similar histopathology between the so‐called post‐traumatic synovitis and OA has been described, again suggesting the importance of mechanical stress in progressive loss of cartilage (Soren et al., 1976). Currently, OA is believed to be a very complex multifactorial disease that involves low‐grade inflammation in cartilage and synovium and results in the loss of joint structure and progressive deterioration of cartilage. In April 2015, OA Research Society International confirmed a new understanding of the disease by publishing an updated definition of the disease as follows: OA is a disorder involving moveable joints characterized by cell stress and extracellular matrix degradation initiated by micro‐ and macro‐injury that activates maladaptive repair responses including pro‐inflammatory pathways of innate immunity. The disease manifests first as a molecular derangement (abnormal joint tissue metabolism) followed by anatomical, and/or physiological derangements (characterized by cartilage degradation, bone remodelling, osteophyte formation, joint inflammation and loss of normal joint function), that can culminate in illness (Kraus et al., 2015). It is additionally becoming clear that many of the physiological ailments of ageing are at least associated with, if not directly related to, chronic low‐grade inflammation. Given its role in numerous chronic diseases, chronic inflammation should now be considered a key driver of progressive degeneration in OA joints. Increasingly, attention has turned to the role of the synovium in OA, as it is now proposed that synovitis is common and associated with OA pain.

A set of data from the Chapman group identified that the cannabinoid receptor system present in the synovium may be an important therapeutic target for the treatment of pain and inflammation associated with OA (Richardson et al., 2008). These authors not only demonstrated the presence of an active endocannabinoid system, including endocannabinoids, entourage compounds, CB1 and CB2 receptors and fatty acid amide hydrolase (FAAH), in the knee synovia of patients with end‐stage OA and RA but also provided strong support for functionally coupled cannabinoid receptors in the fibroblast‐like cells derived from synovia from OA and RA patients. In a series of experiments, the non‐selective cannabinoid receptor agonist HU‐210 produced phosphorylation of the downstream signalling kinases, indicating an increase in ERK and p38‐MAPK activity. These pharmacological studies provide strong support for functionally coupled cannabinoid receptors in the fibroblast‐like cells derived from synovia of OA patients (Richardson et al., 2008).

The synovium is the most important site of cytokine production in arthritis, and synovial cells from arthritic animals are known to spontaneously produce large amounts of TNFα when cultured in vitro (Malfait et al., 1998). This broad family of secreted small proteins is crucial in cell communication during inflammation. A board spectrum of pro‐inflammatory cytokines in the synovial fluid of OA patients can be detected easily (Schlaak et al., 1996). In vitro studies have demonstrated that exposure of naive synoviocytes to pro‐inflammatory cytokines leads to an up‐regulation of CB1 receptors but a down‐regulation of CB2 receptors (McPartland, 2008). Additional in vitro studies showed that synovial cells from mice with inflammatory arthritis produced large amounts of TNFα (Malfait et al., 2000), which is the main contributor to inflammation in arthritis.

A significant amount of research has clarified the contribution made by the synovium to RA, but more research is needed to elucidate its contribution in OA pathology, which has long been underestimated. In fact, the synovium as a whole has received less attention than have the other joint tissues, partly due to the former's relative inaccessibility and fragility in a typical rodent model. A well‐established contributor of joint inflammation is the infiltration of synovial macrophages. Macrophages express CB2 receptors, and cannabinoid receptors are expressed on neuronal cells. Therefore, there is a scope for a complex pattern of cannabinoid interactions within the synovium and surrounding joint tissue.

The enthusiasm for using cannabinoids as medicines seems to go through phases. The separation of CB1 and CB2 receptors implies that the activation of CB2 receptors will lack psychotropic effects, so considerable efforts have gone into selective ligands for this receptor in particular. Fukuda et al. (2014) tested the efficacy of the selective CB2 agonist JWH133 against fibroblast‐like synoviocytes (FLS) inflammation. The authors' encouraging results show that in vitro the FLS culture from RA patients produces IL‐6, MMP3 and chemokine (C‐C motif) ligand 2 (CCL2) in response to TNFα stimulation. This is interesting at a number of levels. IL‐6 is known to induce pain (Alvarez and Levine, 2014) along with MMP3 having a role in matrix turn over, which may diffuse from the synovium into cartilage in parallel to MMP13 (Moore et al., 2000). Fukoda et al. also showed that JWH133 was able to inhibit CCL2 expression, which is a chemokine involved in the recruitment of monocytes, macrophages, T‐cells and dendritic cells to sites of inflammation. Inhibitory effects of CB2 receptors on synovial fibroblasts in RA were also reported by Gui et al. (2014). In FLS isolated from RA patients, pro‐inflammatory mediators up‐regulate the expression of CB2 receptors, negatively regulating the production of pro‐inflammatory cytokines and MMPs. These data suggest that the CB2 receptor may be a potential therapeutic target of RA. Thus activation of the cannabinoid receptor system might be an adaptation to the pro‐inflammatory environment in RA and might help resolve inflammation, although a question arises of whether this is true in OA.

Recently, anti‐inflammatory effects of AEA in synovial cells both from RA and OA‐patients were reported to be mediated by TRPV1 in a COX‐2‐dependent manner. A possible anti‐inflammatory mechanism involves the down‐regulation of MAPK signalling by AEA. Activation of the endocannabinoid system can be beneficial in arthritis, and manipulating this system (especially by using a combination of COX‐2 and a FAAH inhibitor) might be a promising strategy to reduce erosions and inflammation in arthritis (Lowin et al., 2015). This emphasizes the importance of elucidating the involvement of the endocannabinoid signalling in OA in further detail. Future research should also concentrate on phytocannabinnoids. CBD has very strong anti‐inflammatory properties. Synovial cells from mice treated with exogenous CBD produced significantly less TNFα in culture (Malfait et al., 2000). CBD had a dose‐dependent therapeutic effect on disease progression in mice with inflammatory arthritis. The CBD treatment not only suppressed clinical signs of the disease, but no obvious side effects were noted with chronic treatment (Malfait et al., 2000). Furthermore, CBD treatment protected the hind paws from these mice from joint destruction in both acute and chronic disease states when compared to control (Malfait et al., 2000).

The above evidence supports the possibility of using cannabinoids as a novel therapeutic target and/or potential drug in the progression of rheumatic disease states. The question arises as to how to modulate the EC system for the treatment of OA. We believe that in light of data investigating the role of the endocannabinoid system in RA, its modulation will be a treatment for OA as well. CB1 antagonists might reverse the metabolic alterations associated with OA, while activation of CB2 receptors might be beneficial in patients by down‐regulating cytokine production. As cytokines are highly important in OA, they are promising candidate biomarkers for disease diagnosis and prognosis and are subjects for modulation by endocannabinoids. There is a great need for further work on this issue, which, to a certain degree, may be achieved by undertaking future research.

Summary

The originating event accountable for the development of OA is still not known. It is highly probable that, disregarding the initial events, all three tissues mentioned here contribute to OA progression. It was shown that the factors released by osteoblasts might modify chondrocyte differentiation and proliferation (Sanchez et al., 2005). Although the role of the cannabinoid system in joint functioning is well documented in preclinical studies, the evidence from clinical studies is still insufficient to conclude what effects cannabinoids have on OA progression and treatment. OA, therefore, may not be a single disease but may be the outcome of different pathological processes. In one case, OA may be caused by a process restricted to the cartilage, while in another, synovial involvement may be more important with apparent inflammation. Understanding these possible cellular and molecular interactions, particularly between cartilage and bone leading to the progression of OA, represents an important issue in directing treatment to either compartment (bone or cartilage) and may provide a circuit breaker in OA to prevent or slow the progression of this condition. The expression of cannabinoid receptors was higher in chondrocytes than it was in osteocytes, suggesting that chondrocytes may be more responsive to cannabinoid treatment, thus facilitating the chondroprotective effects. Despite this, none of the clinical trials conducted so far have included observations on the effect of cannabinoids on the progression of cartilage, bone or synovium impairments in OA. Likewise, limited evidence is available to support the medical use of cannabinoids in OA‐related pain. The most notable clinical studies aimed at modulating the endocannabinoid system for the alleviation of OA pain were conducted with the irreversible FAAH inhibitor, PF‐04457845 (Huggins et al., 2012). This compound showed excellent tolerability and elevated the plasma levels of AEA. However, despite the analgesic properties of FAAH inhibition in rodent models of OA pain (Schuelert et al., 2011), it failed to provide analgesia in knee OA patients (Huggins et al., 2012). There are possible explanations for the lack of an analgesic effect, but further studies of this type are necessary (for details, see Malek and Starowicz, 2016). The main problem in the translation of results from animal models to clinical applications might be the mechanisms underlying OA. As the mechanisms are still not fully understood, they limit the direct conversion of the data from preclinical work and raise a question of how OA patients can be divided into diverse subgroups based on the origin and development of the disease.

To sum up, as in vitro studies reveal promising data about a potential role of the endocannabinoid system in the modulation of the mechanisms underlying structural pathology during OA, including their possible involvement in the repair mechanisms, further studies exploring the overall in vivo effects of these agents in preclinical models are necessary to support the potential interest of cannabinoids for halting the progression of this disease.

Nomenclature of Targets and Ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Harding et al., 2018), and are permanently archived in the Concise Guide to PHARMACOLOGY 2017/18 (Alexander et al., 2017a,b,c).

Conflict of interest

The authors declare that there are no conflicts of interest.

Acknowledgements

This work was supported by the National Science Centre, Krakow, Poland, by grant 2014/13/B/NZ7/02311, and by the Ministry of Science and Higher Education, Warsaw, Poland, by grant 0044/DIA/2013/42 from and statutory funds. N.M. is a recipient of a START scholarship funded by the Foundation for Polish Science. The Authors express their gratitude to Magdalena Kostrzewa and Agnieszka Pająk who contributed to the intellectual design of 2014/13/B/NZ7/02311.

Malek, N. , and Starowicz, K. (2019) Joint problems arising from lack of repair mechanisms: can cannabinoids help?. British Journal of Pharmacology, 176: 1412–1420. 10.1111/bph.14204.

References

  1. Aigner T, Bartnik E, Sohler F, Zimmer R (2004). Functional genomics of osteoarthritis: on the way to evaluate disease hypotheses. Clin Orthop Relat Res (427 Suppl): S138–S143. [PubMed] [Google Scholar]
  2. Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Marrion NV, Peters JA et al (2017a). The Concise Guide to PHARMACOLOGY 2017/18: G protein‐coupled receptors. Br J Pharmacol 174: S17–S129. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Alexander SPH, Fabbro D, Kelly E, Marrion NV, Peters JA, Faccenda E et al (2017b). The Concise Guide to PHARMACOLOGY 2017/18: Enzymes. Br J Pharmacol 174: S272–S359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Alexander SPH, Striessnig J, Kelly E, Marrion NV, Peters JA, Faccenda E et al (2017c). The Concise Guide to PHARMACOLOGY 2017/18: Voltage‐gated ion channels. Br J Pharmacol 174: S160–S194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Alvarez P, Levine JD (2014). Screening the role of pronociceptive molecules in a rodent model of endometriosis pain. J Pain 15: 726–733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Buckwalter JA, Mankin HJ (1998). Articular cartilage repair and transplantation. Arthritis Rheum 41: 1331–1342. [DOI] [PubMed] [Google Scholar]
  7. Dunn SL, Wilkinson JM, Crawford A, Bunning RAD, Le Maitre CL (2016). Expression of cannabinoid receptors in human osteoarthritic cartilage: implications for future therapies. Cannabis Cannabinoid Res 1: 3–15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dunn SL, Wilkinson JM, Crawford A, Le Maitre CL, Bunning RAD (2014). Cannabinoid WIN‐55,212‐2 mesylate inhibits interleukin‐1β induced matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase expression in human chondrocytes. Osteoarthritis Cartilage 22: 133–144. [DOI] [PubMed] [Google Scholar]
  9. Dunn SL, Wilkinson JM, Crawford A, Le Maitre CL, Bunning RAD (2012). Cannabinoids: novel therapies for arthritis? Future Med Chem 4: 713–725. [DOI] [PubMed] [Google Scholar]
  10. Fukuda S, Kohsaka H, Takayasu A, Yokoyama W, Miyabe C, Miyabe Y et al (2014). Cannabinoid receptor 2 as a potential therapeutic target in rheumatoid arthritis. BMC Musculoskelet Disord 15: 275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Funck‐Brentano T, Cohen‐Solal M (2015). Subchondral bone and osteoarthritis. Curr Opin Rheumatol 27: 420–426. [DOI] [PubMed] [Google Scholar]
  12. Gavenis K, Schumacher C, Schneider U, Eisfeld J, Mollenhauer J, Schmidt‐Rohlfing B (2009). Expression of ion channels of the TRP family in articular chondrocytes from osteoarthritic patients: changes between native and in vitro propagated chondrocytes. Mol Cell Biochem 321: 135–143. [DOI] [PubMed] [Google Scholar]
  13. Goldring MB (2000a). Osteoarthritis and cartilage: the role of cytokines. Curr Rheumatol Rep 2: 459–465. [DOI] [PubMed] [Google Scholar]
  14. Goldring MB (2000b). The role of the chondrocyte in osteoarthritis. Arthritis Rheum 43: 1916–1926. [DOI] [PubMed] [Google Scholar]
  15. Goldring MB, Marcu KB (2009). Cartilage homeostasis in health and rheumatic diseases. Arthritis Res Ther 11: 224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gómez R, Conde J, Scotece M, López V, Lago F, Gómez Reino JJ et al (2014). Endogenous cannabinoid anandamide impairs cell growth and induces apoptosis in chondrocytes. J Orthop Res 32: 1137–1146. [DOI] [PubMed] [Google Scholar]
  17. Gui H, Liu X, Wang Z‐W, He D‐Y, Su D‐F, Dai S‐M (2014). Expression of cannabinoid receptor 2 and its inhibitory effects on synovial fibroblasts in rheumatoid arthritis. Rheumatology (Oxford) 53: 802–809. [DOI] [PubMed] [Google Scholar]
  18. Harding SD, Sharman JL, Faccenda E, Southan C, Pawson AJ, Ireland S et al (2018). The IUPHAR/BPS Guide to PHARMACOLOGY in 2018: updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY. Nucl Acids Res 46: D1091–D1106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Huggins JP, Smart TS, Langman S, Taylor L, Young T (2012). An efficient randomised, placebo‐controlled clinical trial with the irreversible fatty acid amide hydrolase‐1 inhibitor PF‐04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee. Pain 153: 1837–1846. [DOI] [PubMed] [Google Scholar]
  20. Idris AI, Ralston SH (2012). Role of cannabinoids in the regulation of bone remodeling. Front Endocrinol (Lausanne) 3: 136. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Idris AI, Sophocleous A, Landao‐Bassonga E, Canals M, Milligan G, Baker D et al (2009). Cannabinoid receptor type 1 protects against age‐related osteoporosis by regulating osteoblast and adipocyte differentiation in marrow stromal cells. Cell Metab 10: 139–147. [DOI] [PubMed] [Google Scholar]
  22. Idris AI, Sophocleous A, Landao‐Bassonga E, van't Hof RJ, Ralston SH (2008). Regulation of bone mass, osteoclast function, and ovariectomy‐induced bone loss by the type 2 cannabinoid receptor. Endocrinology 149: 5619–5626. [DOI] [PubMed] [Google Scholar]
  23. Idris AI, van't Hof RJ, Greig IR, Ridge SA, Baker D, Ross RA et al (2005). Regulation of bone mass, bone loss and osteoclast activity by cannabinoid receptors. Nat Med 11: 774–779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kraus VB, Blanco FJ, Englund M, Karsdal MA, Lohmander LS (2015). Call for standardized definitions of osteoarthritis and risk stratification for clinical trials and clinical use. Osteoarthritis Cartilage 23: 1233–1241. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Krustev E, Rioux D, McDougall JJ (2015). Mechanisms and mediators that drive arthritis pain. Curr Osteoporos Rep 13: 216–224. [DOI] [PubMed] [Google Scholar]
  26. Lian JB, Javed A, Zaidi SK, Lengner C, Montecino M, van Wijnen AJ et al (2004). Regulatory controls for osteoblast growth and differentiation: role of Runx/Cbfa/AML factors. Crit Rev Eukaryot Gene Expr 14: 1–41. [PubMed] [Google Scholar]
  27. Lories RJU, Luyten FP (2012). Osteoarthritis, a disease bridging development and regeneration. Bonekey Rep 1: 136. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lowin T, Apitz M, Anders S, Straub RH (2015). Anti‐inflammatory effects of N‐acylethanolamines in rheumatoid arthritis synovial cells are mediated by TRPV1 and TRPA1 in a COX‐2 dependent manner. Arthritis Res Ther 17: 321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lubberts E, Joosten LA, Helsen MM, van den Berg WB (1998). Regulatory role of interleukin 10 in joint inflammation and cartilage destruction in murine streptococcal cell wall (SCW) arthritis. More therapeutic benefit with IL‐4/IL‐10 combination therapy than with IL‐10 treatment alone. Cytokine 10: 361–369. [DOI] [PubMed] [Google Scholar]
  30. Malek N, Popiolek‐Barczyk K, Mika J, Przewlocka B, Starowicz K (2015). Anandamide, acting via cb2 receptors, alleviates LPS‐induced neuroinflammation in rat primary microglial cultures. Neural Plast 2015: 130639–130610. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Malek N, Starowicz K (2016). Dual‐acting compounds targeting endocannabinoid and endovanilloid systems – a novel treatment option for chronic pain management. Front Pharmacol 7: 257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Malfait AM, Butler DM, Presky DH, Maini RN, Brennan FM, Feldmann M (1998). Blockade of IL‐12 during the induction of collagen‐induced arthritis (CIA) markedly attenuates the severity of the arthritis. Clin Exp Immunol 111: 377–383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Malfait AM, Gallily R, Sumariwalla PF, Malik AS, Andreakos E, Mechoulam R et al (2000). The nonpsychoactive cannabis constituent cannabidiol is an oral anti‐arthritic therapeutic in murine collagen‐induced arthritis. Proc Natl Acad Sci U S A 97: 9561–9566. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990). Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346: 561–564. [DOI] [PubMed] [Google Scholar]
  35. Mbvundula EC, Bunning RAD, Rainsford KD (2006). Arthritis and cannabinoids: HU‐210 and Win‐55,212‐2 prevent IL‐1alpha‐induced matrix degradation in bovine articular chondrocytes in‐vitro. J Pharm Pharmacol 58: 351–358. [DOI] [PubMed] [Google Scholar]
  36. Mbvundula EC, Bunning RAD, Rainsford KD (2005). Effects of cannabinoids on nitric oxide production by chondrocytes and proteoglycan degradation in cartilage. Biochem Pharmacol 69: 635–640. [DOI] [PubMed] [Google Scholar]
  37. McDougall JJ, Muley MM, Philpott HT, Reid A, Krustev E (2017). Early blockade of joint inflammation with a fatty acid amide hydrolase inhibitor decreases end‐stage osteoarthritis pain and peripheral neuropathy in mice. Arthritis Res Ther 19: 106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. McDougall JJ, Yu V, Thomson J (2008). In vivo effects of CB2 receptor‐selective cannabinoids on the vasculature of normal and arthritic rat knee joints. Br J Pharmacol 153: 358–366. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. McPartland JM (2008). Expression of the endocannabinoid system in fibroblasts and myofascial tissues. J Bodyw Mov Ther 12: 169–182. [DOI] [PubMed] [Google Scholar]
  40. Milner JM, Cawston TE (2005). Matrix metalloproteinase knockout studies and the potential use of matrix metalloproteinase inhibitors in the rheumatic diseases. Curr Drug Targets Inflamm Allergy 4: 363–375. [DOI] [PubMed] [Google Scholar]
  41. Moore BA, Aznavoorian S, Engler JA, Windsor LJ (2000). Induction of collagenase‐3 (MMP‐13) in rheumatoid arthritis synovial fibroblasts. Biochim Biophys Acta 1502: 307–318. [DOI] [PubMed] [Google Scholar]
  42. Munro S, Thomas KL, Abu‐Shaar M (1993). Molecular characterization of a peripheral receptor for cannabinoids. Nature 365: 61–65. [DOI] [PubMed] [Google Scholar]
  43. Ofek O, Karsak M, Leclerc N, Fogel M, Frenkel B, Wright K et al (2006). Peripheral cannabinoid receptor, CB2, regulates bone mass. Proc Natl Acad Sci U S A 103: 696–701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Priano F (2017). Early efficacy of intra‐articular HYADD® 4 (Hymovis®) injections for symptomatic knee osteoarthritis. Joints 5: 79–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Raynauld J‐P, Martel‐Pelletier J, Berthiaume M‐J, Beaudoin G, Choquette D, Haraoui B et al (2006). Long term evaluation of disease progression through the quantitative magnetic resonance imaging of symptomatic knee osteoarthritis patients: correlation with clinical symptoms and radiographic changes. Arthritis Res Ther 8: R21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Richardson D, Pearson RG, Kurian N, Latif ML, Garle MJ, Barrett DA et al (2008). Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis. Arthritis Res Ther 10: R43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Robinson WH, Lepus CM, Wang Q, Raghu H, Mao R, Lindstrom TM et al (2016). Low‐grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat Rev Rheumatol 12: 580–592. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Rossi F, Siniscalco D, Luongo L, De Petrocellis L, Bellini G, Petrosino S et al (2009). The endovanilloid/endocannabinoid system in human osteoclasts: possible involvement in bone formation and resorption. Bone 44: 476–484. [DOI] [PubMed] [Google Scholar]
  49. Russo EB (2016). Beyond cannabis: plants and the endocannabinoid system. Trends Pharmacol Sci 37: 594–605. [DOI] [PubMed] [Google Scholar]
  50. Sanchez C, Deberg MA, Piccardi N, Msika P, Reginster J‐YL, Henrotin YE (2005). Subchondral bone osteoblasts induce phenotypic changes in human osteoarthritic chondrocytes. Osteoarthritis Cartilage 13: 988–997. [DOI] [PubMed] [Google Scholar]
  51. Sarzi‐Puttini P, Cimmino MA, Scarpa R, Caporali R, Parazzini F, Zaninelli A et al (2005). Osteoarthritis: an overview of the disease and its treatment strategies. Semin Arthritis Rheum 35: 1–10. [DOI] [PubMed] [Google Scholar]
  52. Schlaak JF, Pfers I, Meyer Zum Büschenfelde KH, Märker‐Hermann E (1996). Different cytokine profiles in the synovial fluid of patients with osteoarthritis, rheumatoid arthritis and seronegative spondylarthropathies. Clin Exp Rheumatol 14: 155–162. [PubMed] [Google Scholar]
  53. Schuelert N, Johnson MP, Oskins JL, Jassal K, Chambers MG, McDougall JJ (2011). Local application of the endocannabinoid hydrolysis inhibitor URB597 reduces nociception in spontaneous and chemically induced models of osteoarthritis. Pain 152: 975–981. [DOI] [PubMed] [Google Scholar]
  54. Schuelert N, McDougall JJ (2009). Grading of monosodium iodoacetate‐induced osteoarthritis reveals a concentration‐dependent sensitization of nociceptors in the knee joint of the rat. Neurosci Lett 465: 184–188. [DOI] [PubMed] [Google Scholar]
  55. Sharma AR, Jagga S, Lee S‐S, Nam J‐S (2013). Interplay between cartilage and subchondral bone contributing to pathogenesis of osteoarthritis. Int J Mol Sci 14: 19805–19830. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Smith MD, Triantafillou S, Parker A, Youssef PP, Coleman M (1997). Synovial membrane inflammation and cytokine production in patients with early osteoarthritis. J Rheumatol 24: 365–371. [PubMed] [Google Scholar]
  57. Sofat N, Kuttapitiya A (2014). Future directions for the management of pain in osteoarthritis. Int J Clin Rheumtol 9: 197–276. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Sophocleous A, Börjesson AE, Salter DM, Ralston SH (2015). The type 2 cannabinoid receptor regulates susceptibility to osteoarthritis in mice. Osteoarthritis Cartilage 23: 1586–1594. [DOI] [PubMed] [Google Scholar]
  59. Soren A, Klein W, Huth F (1976). Microscopic comparison of the synovial changes in posttraumatic synovitis and osteoarthritis. Clin Orthop Relat Res (121): 191–195. [PubMed] [Google Scholar]
  60. Tam J, Ofek O, Fride E, Ledent C, Gabet Y, Müller R et al (2006). Involvement of neuronal cannabinoid receptor CB1 in regulation of bone mass and bone remodeling. Mol Pharmacol 70: 786–792. [DOI] [PubMed] [Google Scholar]
  61. Valverde O, Karsak M, Zimmer A (2005). Analysis of the endocannabinoid system by using CB1 cannabinoid receptor knockout mice. Handb Exp Pharmacol (168): 117–145. [DOI] [PubMed] [Google Scholar]
  62. Wei B, Zhu Z, Xiang M, Song L, Guo W, Lin H et al (2017). Corticosterone suppresses IL‐1β‐induced mPGE2 expression through regulation of the 11β‐HSD1 bioactivity of synovial fibroblasts in vitro . Exp Ther Med 13: 2161–2168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Whyte LS, Ford L, Ridge SA, Cameron GA, Rogers MJ, Ross RA (2012). Cannabinoids and bone: endocannabinoids modulate human osteoclast function in vitro . Br J Pharmacol 165: 2584–2597. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES