Emerging pharmaceutical therapeutics and delivery technologies for osteoarthritis therapy

Abstract

Introduction

There are more than 400 million patients affected by osteoarthritis (OA) worldwide, with a global total prevalence of OA of 15%, causing significant economic burdens (Hiligsmann et al., 2013). OA is resulted from a combination of risk factors such as age, obesity, knee malalignment, biomechanical loading of joints, low-grade systemic inflammation, etc. At present, non-pharmacological approaches and surgical therapies are the most commonly used treatments for OA. Pharmaceutical treatments recommended by international guidelines to treat OA can merely alleviate symptoms or have obvious side effects if long-term use (Robinson et al., 2018; Ferguson et al., 2018; van de Graaf et al., 2018; Ferreira et al., 2019). Therefore, it is urgent to develop novel therapeutics to treat OA. In the past years, more and more therapeutic molecules, including many natural compounds isolated from medicinal plants, as well as multiple new delivery technologies to increase the absorption and decrease the side effects of the therapeutic candidates have been investigated This review summarized the progress of these emerging pharmaceutical therapeutics and the delivery technologies, with the therapeutic effects of active molecules extracted from traditional Chinese medicine are highlighted, with the expectation to identify much more alternatives and new options for the treatment of OA.

Pathophysiology of osteoarthritis

OA is a whole joint disease that affects the hyaline articular cartilage, subchondral bone, ligaments, capsule, synovium and periarticular muscles (Martel-Pelletier et al., 2016). The integrity of cartilage structure is damaged during the OA process, making cartilage more vulnerable to external stimulation (Loeser et al., 2016; Hunter and Bierma-Zeinstra, 2019). At the initial stage, articular cartilage was degraded from the cartilage surface and cracks emerged gradually, then enlarged into the cartilage calcification area. The degradation products and pro-inflammatory mediators released during this process induced synovial hyperplasia and inflammatory response in the surrounding synovium, as well as vascular infiltration in the subchondral bone. Although hypertrophic chondrocytes began to proliferate in an attempt to repair cartilage, the self-repair ability of articular cartilage is limited, resulting in the development of OA, expressed as the changes in the structure and properties of articular cartilage. The scheme of the main pathophysiology of OA is shown in Figure 1.

Open in a separate window

FIGURE 1

The pathophysiology of OA.

Inflammation is thought to play an important role in the formation and progression of OA. There is a clear link between the progression of cartilage degeneration and the existence of reactive or inflammatory synovium (Felson, 2006). For example, inflammatory substances like proinflammatory cytokines are important mediators of the altered metabolism and increased catabolism of joint tissue in OA (Ayral et al., 2005; Pozgan et al., 2010). Among them, IL-1β, TNF, and IL-6 are several main proinflammatory cytokines involved. Particularly, IL-1 has been found to accelerate cartilage degradation and nociceptive pathway stimulation by activating the nuclear factor kappa-B (NF-ĸB) pathway (Benito et al., 2005). IL-1 is produced by chondrocytes and synovial nucleated cells in patients with OA, and IL-1 stimulated Matrix metalloproteinase (MMP)-1 and MMP-13 expression in chondrocytes (Mengshol et al., 2000). TNF-α has been found to be elevated in the synovial fluid, synovial membrane, subchondral bone, and cartilage of OA patients in various studies (Stannus et al., 2010; Xue et al., 2013). In-articular chondrocytes, TNF-α upregulates MMP-13 and stimulates the production of iNOS, cyclooxygenase (COX)-2, IL-6, and PGE2 (Guerne et al., 1990, Séguin and Bernier, 2003; El Mansouri et al., 2011), while suppressing the synthesis of type II collagen, proteoglycans, and proteoglycan-binding proteins (Xue et al., 2013). TNF-α blocks mesenchymal stem cells (MSCs) differentiation into osteoblasts by Notch activation (Zhao, 2017) and can regulate bone remodeling. IL-6 also associates with joint tissue hyperalgesia and hypersensitivity, as well as cartilage degeneration (Brenn et al., 2007) such as by inhibiting type II collagen formation while increasing the production of MMPs (Rowan et al., 2001; Porée et al., 2008). The IL-6-activated JAK/STAT and mitogen-activated protein kinase (MAPK) pathways have been found to upregulate the level of MMP-1, MMP-3, and MMP-13 in human chondrocytes (Aida et al., 2012). IL-6 also has been discovered to have a key function in mediating effects on the subchondral bone layer (Chenoufi et al., 2001; Kwan Tat et al., 2004; Sakao et al., 2009). TGF-β was demonstrated to be able to suppress hypertrophy in MSCs and articular chondrocytes (Yang et al., 2001; Zhang et al., 2004). TGF-β binds to heterotypic TGF receptors in chondrocytes, causing the phosphorylation of the heteromeric SMAD2/3/4 complex. The active small molecules against decapentaplegic (SMAD) complex subsequently translocates to the nucleus, where it interacts with co-transcription factors to control gene transcription, including chondrogenesis stimulation and degeneration and mineralization suppression (Harradine and Akhurst, 2006; Chen et al., 2012; Shen et al., 2013). Leptin is primarily produced by adipocytes, and it can help chondrocytes in the growth plate proliferate and differentiate (Wang et al., 2012). Through the JAK/STAT and MAPK pathways, it can stimulate chondrocytes (Ben-Eliezer et al., 2007) and is essential for chondrocyte hypertrophy (Kishida et al., 2005; Simopoulou et al., 2007). During OA, leptin can also upregulate the expression of MMPs, resulting in cartilage degradation (Toussirot et al., 2007; Vuolteenaho et al., 2009; Koskinen et al., 2011). Leptin binds to hypothalamic receptors and activates osteoblasts via β2 adrenergic receptors in the central route (Takeda et al., 2002). It can inhibit osteoblast proliferation, and boost bone resorption of osteoclasts (Fu et al., 2005). Within the peripheral pathway, leptin binds to human MSCs, promoting proliferation and differentiation into osteoblasts (Astudillo et al., 2008). In the past several years, exosomes were shown to be able to facilitate cell-to-cell communication and control a variety of biological processes such as immune response and inflammation (Salvi et al., 2018; Console et al., 2019). Because of its direct and close contact with the synovial membrane, articular cartilage, and other types of joint tissue, exosomes contained in the synovial fluid is valuable for monitoring pathological changes in the joint area (Kolhe et al., 2017). However, relevant research is still in its early stages, and the molecular mechanism of exosome-receptor cell contact remains further investigation. Cytokines and mechanisms related to OA are shown in Figure 2.

Open in a separate window

FIGURE 2

Cytokines and mechanism of OA.

Active ingredients of medicinal plants for osteoarthritis

In clinic, antipyretic analgesics, NSAIDs, opioids, and GCs are frequently used to treat OA. However, these medications are just symptomatic and have several negative effects. An increased risk of gastrointestinal bleeding and a slight rise in systolic blood pressure are two adverse effects for which there is solid evidence (Evans et al., 2014; Maudens et al., 2018; Zhang et al., 2020b). Insulin resistance, muscular and skin atrophies, depression, and severe skeletal consequences are all examples of GCs. As a result, developing a new drug candidate and/or improving the drug delivery safety and efficacy is critical for the treatment of OA. Traditional Chinese medicine has long been used to treat a variety of ailments, and it has the benefits of being affordable, widely available, and have fewer adverse effects (Song et al., 2018). Scholars looked into the treatment potential of traditional Chinese medications for OA, and the findings revealed that they are both effective and safe (Liu et al., 2013; Chen et al., 2017).

Matrine is an alkaloid obtained from the traditional Chinese medicine Sophora flavescens Aiton. Basic research on matrine’s anti-inflammatory properties is currently in substantial volume, indicating that matrine possesses pharmacological activity and therapeutic application potential (Zhang et al., 2020a). Matrine inhibits MAPK and NF-κB activation in human chondrocytes in vitro and reduces IL-1β-induced MMP synthesis, protecting chondrocytes against extracellular matrix degradation by MMPs (Lu et al., 2015).

Sinomenine is a bioactive alkaloid produced from the Chinese medicinal plant Sabia japonica Maxim. Sinomenine reduces the number of CD11bF4/80CD64 synovial macrophages and CD11bLy6CCD43 monocytes/macrophages in CIA mice. In CIA mice, a decrease in the quantity of these macrophages suppresses the release of inflammatory cytokines. Sinomenine can thereby control the inflammatory response by inhibiting the activities of IL-1α, IL-1β, TNF-α, and IL-6 (Liu et al., 2018; Gao et al., 2019).

Osthole is a natural coumarin derived from the Cnidium monnieri (L.) Cuss that is extensively used in Traditional Chinese Medicine clinical practice. Recent research has discovered that osthole possesses antioxidant, anticancer, anti-inflammatory, and immunomodulatory properties (Wang et al., 2007; You et al., 2009; Zhang et al., 2015). Excessive stimulation of the PI3K/Akt pathway has been demonstrated to increase MMP expression in previous investigations (Katsara et al., 2017). Inflammation, immunological response, and apoptosis are all regulated by the NF-κB pathway. Researchers have discovered that osthole can drastically lower critical proteins in the PI3K/Akt/NF-κB pathway, hence alleviating OA. Toll-like receptor 4 (TLR4) activation is linked to chondrocyte inflammation and catabolism, according to researchers (Yan et al., 2019). TLR4 and its downstream NF-κB are inhibited by curcumin, which reduces synovial inflammation.

Curcumin, extract from Curcuma longa L. can also protect chondrocytes and maintain cartilage homeostasis by activating the ERK1/2 pathway and inhibiting the Akt/mTOR pathway (Zhang et al., 2018). Curcumin’s anti-OA properties can possibly be attributed to other factors. Curcumin, for example, can decrease chondrocyte death and enhance chondrocyte proliferation by mediating the Wnt/β-Catenin pathway (Wang et al., 2017). Inhibiting NF-κB signal transduction can also diminish chondrocyte extracellular matrix breakdown.

Loganin is a prominent iridoid glycoside and one of Strychnos nux-vomica L.’ quality control indicators. Loganin can boost Col2a1 expression while lowering MMP-3, MMP-13, Col10, cryopyrin, and caspase-1 expression in cartilage (Hu et al., 2020). In subchondral bone, loganin reduced the expression of CD31 and endomucin. Furthermore, loganin inhibited p65 protein nuclear translocation and decreased the quantity of p-IκB in chondrocytes (Yang et al., 2019). According to these findings, Loganin suppresses NF-κB signaling and reduces cartilage matrix degradation and chondrocyte pyroptosis in articular cartilage.

Morroniside is a significant iridoid glycoside and one of Cornus officinalis Sieb.et Zucc.’ quality control criteria. Morroniside promotes cartilage matrix formation by increasing collagen type II expression and reducing chondrocyte pyroptosis. Morroniside decreased the synthesis of MMP-13, caspase-1, and nod-like receptor protein-3 (NLRP3) in IL-1β-stimulated chondrocytes (Park et al., 2021). Morroniside also slowed the course of OA by increasing chondrocyte proliferation and decreasing chondrocyte death. Morroniside has been shown to block NF-κB signaling, slowing the development of OA (Yu et al., 2021).

Madecassoside is a triterpenoid component obtained from the Gotu kola plant [Centella asiatica (L.) Urban] that has antioxidative and anti-inflammatory activities. Madecassoside has been demonstrated to successfully suppress IL-1β-induced overexpression of MMP-3, MMP-13, inducible nitric oxide synthase (iNOS), and COX-2, as well as type II collagen and sox9 degradation (Moqbel et al., 2020). Madecassoside was also able to inhibit IL-1β-induced phosphorylation of p65 in osteoarthritic chondrocytes. Furthermore, as compared to the OA group, madecassoside reduced the OARSI score and avoided cartilage deterioration in a rat OA model. These findings demonstrated that madecassoside inhibits the NF-κB signaling pathway, lowering IL-1β-induced chondrocyte inflammation, implying that MA might be used to treat OA patients.

Quercitrin is a yellow-colored flavonoid that is a substantial component of Taxillus sutchuenensis (Lecomte) Danser’ total flavonoids. By stimulating the p110/AKT/mTOR signaling pathway, quercitrin can decrease MMP-13 production and enhance collagen II accumulation, promoting cell proliferation and delaying ECM breakdown (Guo et al., 2021). According to the research, quercitrin targets p110 to produce its anti-OA properties. Grape seed extract contains resveratrol, which is a polyphenol phytoalexin (Xu et al., 2019). Resveratrol can block the degradation of IκB-α and the activation of NF-κB caused by IL-1β.

Resveratrol can significantly reduce the inflammatory response induced by IL-1β in OA chondrocytes, including MMP-13, MMP-3, and MMP-1. Resveratrol can also boost collagen-II and aggrecan levels. As a result, Resveratrol holds a lot of promise in the treatment of OA. Anti-inflammatory and antioxidant effects have been discovered in fraxetin. It is a coumarin chemical isolated from Fraxini Cortex that is frequently utilized and investigated. According to the findings, fraxetin suppressed inflammatory mediator release and prevented chondrocyte death produced by IL-1β through modulating the TLR4/myeloid differentiation primary response 88/NF-κB pathway in chondrocytes (Wang et al., 2020). In addition, fraxetin inhibited MMP-13 overexpression and collagen II breakdown in the ECM. The findings revealed that fraxetin might prevent cartilage from deterioration.

Ligustilide, a key ingredient in the plant Angelicae Sinensis Radix, has anti-inflammatory properties. Ligustilide inhibits NF-κB activation via the PI3K/AKT pathway, reducing IL-1β-induced chondrocyte inflammation and ECM breakdown (Li et al., 2018). In human OA chondrocytes, Ligustilide inhibits the production of PGE2, iNOS, COX-2, MMP-3, MMP-13, and ADAMTS-5, as well as the breakdown of aggrecan and collagen II. Ligustilide has the potential to be an effective OA treatment.

Icariin, an Epimedium extract, has been shown to have anti-osteoporotic and anti-inflammatory properties in OA patients. Icariin might reduce pyroptosis by suppressing the NLRP3 signaling-mediated caspase-1 pathway, which is important in the pathogenesis of OA, to reduce chondrocyte damage and the incidence of OA. Icariin may be a promising target drug for the treatment of OA. Icariin appears to be a viable target drug for treating OA.

Baicalein, which is derived from the Scutellaria baicalensis Georgi, is commonly used in anti-inflammatory treatments. Baicalein might successfully relieve OA by improving chondrocyte apoptotic and catabolic phenotypes and subchondral bone remodeling (Chen et al., 2015). Baicalein was discovered to limit preosteoblast differentiation and proliferation while triggering preosteoblast death, hence controlling subchondral bone remodeling (Li et al., 2021). Baicalein can also reduce vascularisation and synovial cell proliferation, helping to regulate synovitis and ease subchondral bone sclerosis. Baicalein may be an effective treatment for OA since it regulates many targets.

modin is a natural anthraquinone isolated from the root and rhizome of Rheum palmatum L. that has previously been demonstrated to have antibacterial (Kim et al., 2005), anti-cancer (Kaneshiro et al., 2006; Lin et al., 2010) and anti-inflammatory (Alisi et al., 2012) activities. Emodin may have anti-osteoarthritic actions via suppressing the NF-κB and Wnt/β-catenin pathways, which reduce the production of MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5 (161). Cell proliferation, migration, and differentiation, as well as cartilage homeostasis and joint remodeling, are all influenced by the Wnt/β-Catenin pathway. Emodin has the potential to cure OA, according to the findings.

The active chemical found in medicinal plants holds a lot of promise for treating OA. However, further clinical trials are needed to validate their usefulness and safety.

Table 3 shows the therapeutic influence of the above natural products for OA.

Intra-articular injection

As a localized disease, OA may be treated through intra-articular (IA) injections (Gerwin et al., 2006). Intra-articular drug delivery offers a variety of advantages, including higher local bioavailability, less systemic exposure, fewer side effect, and lower cost (Evans et al., 2014; Emami et al., 2018). However, because of the dense avascular cartilage matrix made up of negatively charged glycosaminoglycans (GAGs), medicines injected locally will quickly leave the joint region and disperse and travel slowly. The need for biomaterial-based drug delivery vehicles that can increase medication bioavailability in target tissues notwithstanding the challenges (Maudens et al., 2018). IA injectable formulations of glucocorticoids and hyaluronic acid are available (Zhang et al., 2020b). And the majority of them are in the form of solutions or suspensions. Due to the fast disappearance of classic injectable formulations in joints, new drug delivery methods are expected to be developed yet.

Microspheres can not only protect pharmaceuticals in vivo from numerous causes but also slow down their release. It reduces delivery durations and doses while avoiding the harmful side effects of systemic absorption, providing essential theoretical support for OA research and therapy. Triamcinolone acetonide (TAA), a traditional corticosteroid, relieves synovitis and discomfort, but only temporarily. Local release of TAA based on biomaterials may extend pain relief without the need for numerous injections (Burt et al., 2009).

Scholars discovered that hyaluronic acid nanoparticle/hydrogel (HA-NP) exhibited resistance to hyaluronidase digestion in vitro and long-term retention ability in the knee joint in vivo. The injectable hydrogel-based drug delivery system-dexamethasone hydrogels have a consistent release profile from the start, with a content of 22 percent of the original medication released in 5 days. Furthermore, these drug delivery methods are less cytotoxic and support good cell viability in chondrocytes and osteoblast cells. Intra-articular injection can reduce gastrointestinal reactions, avoid the first-pass effect, and ensure that drugs can be delivered to the articular cavity. However, intra-articular injection needs to puncture the skin, which is invasive and may cause inflammation and bring secondary damage to OA patients. What’s more, 50% of the clinical intra-articular injections will be injected outside the joint cavity. Therefore, it is still necessary to develop new delivery systems to prolong the drug retention time in the joint and reduce the frequency of drug delivery. Above all, Figure 3 have shown oral and intra-articular delivery systems for OA.

Open in a separate window

FIGURE 3

Oral delivery and intra-articular injection systems for OA.

Transdermal delivery

OA is a localized disease that often occurs in the knee, hand and hip joints. Therefore, skin penetration-based topical administration may commonly meet the needs of OA treatment. Transdermal drug administration can allow the medication to enter circulation at a steady pace and continuously via the skin. Compared to the oral route or intra-articular injection, transdermal administration offers a number of benefits (Prausnitz and Langer, 2008). Transdermal administration can minimize administration frequency, improve slow-release effectiveness, and improve patient compliance (Yin and Smith, 2016; Brown and Williams, 2019). However, the stratum corneum, which functions as the first protective layer of the skin and limits medication absorption, poses the biggest obstacle in drug administration via the transdermal method (Hadgraft and Lane, 2005). To enhance the skin penetration of drugs, various physical and chemical means of promoting permeation have been attempted for transdermal delivery of OA drugs.

Numerous chemical enhancers are capable of disrupting the highly ordered bilayer structures of intracellular lipids found in the stratum corneum by inserting amphiphilic molecules into these bilayers to disrupt molecular packing or by extracting lipids using solvents and surfactants to create nanometer-scale lipid packing defects (Prausnitz and Langer, 2008). However, the most significant limitation of this technique is that skin irritation may induce allergic responses in individuals. Iontophoresis is another technique for improving transdermal penetration by supplying an electrical driving force. Due to the fact that iontophoresis does not affect the epidermal barrier directly, it is often applied to tiny charged molecules and certain macromolecules up to a few thousand Daltons (Kalia et al., 2004).

Cavitational ultrasound that uses the bubbles to oscillate and collapse at the skin surface to generate localized shock waves and liquid microjets directed at the stratum corneum induces the disruption in the lipid structure of the stratum corneum and can increase skin permeability for many hours. Additionally, thermal effects from ultrasound have been suggested to impact sonophoretic skin contact favorably by increasing the drug diffusion and the skin permeability coefficients (Canavese et al., 2018; Park et al., 2016).

Articular thermotherapy induces vasodilation and increases blood flow around the joints, thereby reducing pain and joint stiffness (Choi et al., 2015). Besides this, heaters can also help drugs cross the skin. When the thermos therapy is applied, solubility and diffusivity of inorganic and organic drugs increase from the drug-containing layer (Bagherifard et al., 2016). Transdermal drug permeation is increased by the application of heat, which enhances the circulation of bodily fluid, the permeability of blood vessel walls, and the rate-limiting membrane permeability (Lee et al., 2018).

Microneedles are tiny and cheap needles that can carry medications through the skin in the least invasive way (HS et al., 2014; Kennedy et al., 2017). Furthermore, microneedles allow for the regulated and sustained release of medications based on the demands of the patients. Microneedles, in general, could increase skin permeability by creating micron-scale pathways into the skin, and actively drive drugs into the skin either as coated or encapsulated cargo introduced during microneedle insertion or via convective flow through hollow microneedles. Skin penetration enhancement strategies are shown in Figure 4. And we have summarized the advantages and disadvantages between different delivery systems in Table 4.

Open in a separate window

FIGURE 4

Skin penetration enhancement strategies.

TABLE 4

Advantages and disadvantages between different delivery systems.

Administration	Delivery vehicles	Delivered drug	Disadvantages	Advantages
Oral	Microcapsules/Yeast	IL-1β shRNA	Gastrointestinal reaction, high manufacturing cost	Enhance medication absorption, lessen gastrointestinal side effects, lower toxicity, increase bioavailability, good patient compliance
	Liposomes/DOPC, HA	Diclofenac
Intra-articular injection	Microspheres/PEA	Triamcinolone acetonide	Risk of infection, cause patient pain, poor patient compliance, instability, safety of biomaterials	Enhance bioavailability and effectiveness, reducing the injury rate of intra-articular glucocorticoid delivery and the side effects of glucocorticoid drugs. Delay drug release
	Nanospheres/Sodium hyaluronate	HA
Transdermal delivery	Liposomes/Microneedles Liposomes/Ultrasound Liposomes/Thermos therapy	Triptolide	Risk of infection, low drug loading content, allergic responses	Delay drug release, minimize administration frequency, improved drug penetration, reduce joint damage, improve patient compliance
		Diclofenac
		Fentanyl

Open in a separate window

Prospect

OA is a chronic joint disease characterized by degeneration of articular cartilage and hyperosteogeny around the joint. At present, the molecular mechanism of OA is still not clear. The process of modern science and medicine will help us to know better about the pathogenesis of OA and thus more therapeutic targets can be excavated in follow-up work (Rahmati et al., 2017). Lifestyle modification is still the most effective way in the treatment of OA. Doing more exercise to lose weight and keep fit’s not only economical but also can control or slow down the course of OA and reduce the mortality rate of OA. Acetaminophen and NSAIDs are often used in the clinical treatment of OA, but long-term use of these drugs will lead to nephrotoxicity and gastrointestinal reactions. For this reason, it is urgent to develop new drugs for treating OA. Traditional Chinese medicine accumulated a wealth of experience in the treatment of osteoarthritis. At present, many studies that have been focused on the therapeutic effects of active ingredients from medicinal plants, such as ginsenoside, matrine and sinomenine. They were shown to inhibit the expression of pro-inflammatory factors such as IL-1 and TNF-α in diseased tissues, and the downregulation of IL-6 can alleviate the local inflammatory response. Meanwhile, they can also reduce the expression of matrix metalloproteinases to inhibit the interpretation of extracellular matrix of chondrocytes and protect cartilage and according to the current studies, these active ingredients did not show strong cytotoxicity. There is an extensive prospect to explore the application of traditional Chinese medicine in OA.

Another challenge for pharmaceutical treatment in OA lies in the design of cartilage-targeting drug delivery systems. Oral administration frequently leads to fierce gastrointestinal reactions and low bioavailability because of the first-pass effect. Intra-articular injection is an invasive method to the joints. Therefore, various DDSs such as nanoparticles, liposomes and hydrogels based on transdermal/topical delivery systems have caused increasing attention to reducing the frequency of intra-articular injections, increasing patient compliance, and reducing the risks along with the conventional preparations.

Furthermore, as a big challenge to deliver drugs into chondrocytes, we can use physical technologies such as ultrasound and iontophoresis to assist the process of drug delivery and build intelligent local drug delivery systems which help researchers to provide new strategies for the treatment of OA. Besides, new approaches that simultaneously deliver chemical drugs and biological drugs aiming to enhance drug efficacy and reduce the side effects might be also combined to develop the next generation therapeutic system for OA treatment. Because the combination of several different types of drugs may work synergistically, the advanced vehicles that can co-deliver multiple drugs or release them in a responsive manner are highly proposed. However, it presents several new challenges that must be dealt with and a thorough biological assessment is needed for determining the drug combination. Another important aspect is the determination of the best mass ratio of each agent within a co-deliver drugs system which needs a systematic study to investigate the effects of different drug ratios on biological efficacy (Karsdal et al., 2016; Lotz and Caramés, 2011; Hunter, 2011; Vos et al., 2012).

References