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Natural-Compound-Based Treatments for Osteoarthritis
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This entry is adapted from the peer-reviewed paper 10.3390/antiox10020265

Osteoarthritis (OA) is a complex degenerative disease in which joint homeostasis is disrupted, leading to synovial inflammation, cartilage degradation, subchondral bone remodeling, and resulting in pain and joint disability.

osteoarthritis natural products cartilage bone

1. Introduction

Osteoarthritis (OA) is the most common degenerative musculoskeletal disease and is a leading cause of disability in the adult population [1]. OA is a whole-joint disease that is characterized by irreversible cartilage degradation; disruption of the tidemark, accompanied by angiogenesis and cartilage calcification; subchondral bone remodeling; osteophyte formation; mild-to-moderate inflammation of the synovial lining [2][3][4]. The most common risk factors for OA include age, prior joint injury, obesity, muscle atrophy, metabolic disorders, and mechanical stress [5][6]. The disease evolution is typically slow and can take years to develop, with resultant joint pain and stiffness, mobility limitations, and compromised quality of life. Despite the tremendous personal and societal burden of OA, there are no curative treatments available and most conventional therapies (medications, physiotherapy, mechanical devices) provide relatively short-term, unsustained relief of the symptoms [7][8][9][10][11].

Promise exists for emerging disease-modifying drugs in the management of OA patients that regulate cartilage metabolism, subchondral bone remodeling, synovial inflammation, and angiogenesis. Recently, the use of plant-derived natural products has increased because of their therapeutic value in bone health, which is attributable to their chondroprotective and osteoprotective properties [12][13]. Many of these natural products have been reported to have anti-inflammatory and antioxidant properties, anti-catabolic effects on chondrocytes, and inhibitory effects on osteoclast differentiation [14][15][16].

2. Natural-Compound-Based Treatments for OA Therapy

Conventional pharmaceutical agents (steroids or non-steroids anti-inflammatory (NSAIDs) drugs) have small-to-moderate effects in patients with OA [7][9][11][17][18][19]. Accordingly, there is an increasing interest in identifying novel approaches, including the use of natural bioactive components that could promote joint health, and mitigate and/or reverse OA [20].

2.1. Alkaloids

Berberine

Berberine is an alkaloid (benzylisoquinoline) that is found in medicinal plants of the genera Berberis, such as Berberis vulgaris, and is usually found in the roots, rhizomes, and stems (Table 1) [21]. It has been reported that berberine has anti-osteoarthritic effects [21]. In vivo studies in two different OA animal models (collagenase- and surgically induced OA) have demonstrated that berberine has chondroprotective effects, which ameliorates cartilage degradation while inducing chondrocyte proliferation [22][23]. It has been shown that berberine inhibits chondrocyte apoptosis and cartilage degradation via activating AMPK signaling and suppressing p38 MAPK activity [24][25]. Berberine also decreases inflammation and cartilage degradation by modulating the host immune response through the inhibition of TLR4/NF-κB signaling [26]. Moreover, berberine has been associated with bone formation by promoting osteogenic differentiation via activation of Runx-2 and p38 MAPK and reducing osteoclast differentiation [27][28].

Table 1. Natural-alkaloid-based pharmacology therapy for osteoarthritis (OA).

Table

Compound

(Source)

Category

Structure

Therapeutic Target

Treatment

Ref

Berberine

(Berberis vulgaris)

Benzyl

isoquinolin alkaloid

 Antioxidants 10 00265 i001

Activation of AMPK signaling and inhibition of p38 MAPK/NF-κB pathways in chondrocytes.

Activation of p38 MAPK signaling in osteoblasts.

Anti-inflammatory, anti-apoptotic, and anti-degradation in cartilage;

Induction of bone formation.

[22][23][24][25][26][27][28]

2.2. Flavonoids

2.2.1. Apigenin

Apigenin is a flavonoid (4′,5,7-trihydroxyflavone) that is found in herbs (chamomile, thyme), fruits (orange), vegetable oils (extra virgin olive oil), and in plant-based beverages (tea, beer, and wine) (Table 2) [29]. This bioactive agent has already been used as therapeutic therapy against diabetes, cancer, Alzheimer’s disease, and OA [30][31]. Apigenin has anti-inflammatory properties through inhibiting IL-1β/NF-κB and TGFβ/Smad2/3 pathways in chondrocytes [32]. Park et al. have demonstrated that apigenin blocks cartilage degradation in in vitro and in vivo OA mouse models through Hif-2α inhibition and the consequent downregulation of MMP-3, MMP-13, ADAMTS-5, and ADAMTS-4 in articular chondrocytes [33]. Furthermore, apigenin has shown bone protective effects via modulating the gene expression of TGF-β1 and its receptors, BMP-2, BMP-7, ALP, and collagen type I in MG63 osteoblasts [34]. Apigenin also promotes osteogenic differentiation of human mesenchymal stem cells through the JNK and p38 MAPK pathways [35].

2.2.2. Astragalin

Astragalin is a natural flavonoid (kaempferol 3-glucoside) found in various traditional medicinal plants, such as Cuscuta chinensis. Its antioxidant and anti-inflammatory therapeutic properties have led some to consider its potential as a therapeutic agent for OA patients [36][37]. According to Ma et al. [38], astragalin inhibits the IL-1β-stimulated activation of NF-κB and MAPK in the chondrocytes of patients with OA while suppressing inflammation and bone destruction in a mouse model of OA [38][39].

2.2.3. Baicalein

Baicalein is a flavonoid (5,6,7-trihydroxyflavone) that is isolated from the roots of Scutellaria baicalensis and Scutellaria lateriflora and has medicinal properties, including neuroprotective, anti-oxidant, anti-fibrosis, and anti-cancer properties [40][41]. Recently, it has been demonstrated that baicalein has anti-catabolic and anti-apoptotic effects through inhibiting IL-1β induction in chondrocytes [42][43]. Another study showed that the intra-articular injection of medium and high doses of baicalein alleviated OA progression in a rabbit OA model, diminishing cartilage degradation, and showing a lower Mankin score [44]. Similarly, positive results were obtained on bone through the induction of osteoblast differentiation and inhibiting osteoclast differentiation [45][46].

2.2.4. Chrysin

Chrysin is a flavonoid (5,7-dihydroxyflavone) that is found in various medicinal plants, such as Scutellaria baicalensis and Passiflora caerulea, but also in honey and propolis [47]. In human osteoarthritic chondrocytes, chrysin showed a suppressive effect on the IL-1β-induced inflammatory response, including the expression of inducible nitrous oxide synthase (iNOS), COX-2, MMP-1, MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5 via the inhibition of NF-κB signaling and decreases in the concentrations of nitrous oxide (NO) and PGE2. Chrysin also inhibits the degradation of aggrecan and collagen-II [48]. In addition, chrysin attenuates the apoptosis and inflammation of stimulated human OA chondrocytes via the suppression of high-mobility group box chromosomal protein (HMGB-1) [49]. An osteoprotective effect was also observed under chrysin treatment via ERK/MAPK activation and the upregulating of Runx-2 and Osx expression [50][51].

2.2.5. Genistein

Genistein is a flavonoid (isoflavone) and a phytoestrogen that is extracted from Genista tinctoria. It has been reported to have promising benefits in the treatment of several pathologies [52][53][54]. The anti-osteoarthritic activity of genistein is suggested to be due to the relationship between OA and altered estrogen metabolism [55]. Phytoestrogens have some estrogen activity and ameliorate menopausal symptoms, bone loss, and symptoms of OA [56][57]. In vitro, genistein suppresses catabolic effects of IL-1β-induced in human OA chondrocytes by targeting the Nrf2/HO-1 pathway, decreasing the expression of MMPs, nitric oxide synthase 2 (NOS2), and COX-2 [58]. In vivo, genistein attenuated cartilage degradation in two different OA animal models [58][59]. Furthermore, a positive effect on bone was obtained through enhanced osteoblastic differentiation and maturation via the activation of ER (estrogen receptor), p38 MAPK–Runx2, and NO/cGMP pathways [60][61][62]. It also inhibited osteoclast formation and bone resorption by inducing the osteoclastogenic inhibitor osteoprotegerin (OPG) and by blocking NF-κB signaling [60][63].

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