Small molecules of herbal origin for osteoarthritis treatment: in vitro and in vivo evidence

Abstract

Osteoarthritis (OA) is one of the most common musculoskeletal degenerative diseases and contributes to heavy socioeconomic burden. Current pharmacological and conventional non-pharmacological therapies aim at relieving the symptoms like pain and disability rather than modifying the underlying disease. Surgical treatment and ultimately joint replacement arthroplasty are indicated in advanced stages of OA. Since the underlying mechanisms of OA onset and progression have not been fully elucidated yet, the development of novel therapeutics to prevent, halt, or reverse the disease is laborious. Recently, small molecules of herbal origin have been reported to show potent anti-inflammatory, anti-catabolic, and anabolic effects, implying their potential for treatment of OA. Herein, the molecular mechanisms of these small molecules, their effect on physiological or pathological signaling pathways, the advancement of the extraction methods, and their potential clinical translation based on in vitro and in vivo evidence are comprehensively reviewed.

Keywords: Anabolic; Anti-catabolic; Anti-inflammatory; Compound delivery; Herbal extraction; Herbal medicine; Inflammation; Therapeutic target; Traditional Chinese medicine.

Fig. 1

Overview of the healthy and osteoarthritic joint along with the pathophysiology of OA. A Healthy joint is depicted: intact cartilage with no fissures and synovial inflammation signs. Osteoarthritis is characterized by soft tissue swelling, osteophyte formation, meniscus deterioration, and degeneration of cartilage. B Cartilage breakdown products are released from the damaged cartilage tissue into the joint space, which are phagocytosed by the synovial cells and infiltrated macrophages, intensifying synovial inflammation. In the inflamed synovium, pro-inflammatory and catabolic mediators are produced by the activated synovial cells that cause overproduction of the proteolytic enzymes, establishing a positive feedback loop. The activated synovial B cells, T cells, and infiltrating macrophages amplify the inflammatory response. To neutralize this inflammatory response, anti-inflammatory cytokines are produced by the synoviocytes and chondrocytes. Furthermore, the inflamed macrophages contribute to the synovial angiogenesis and osteophyte formation via VEGF and BMPs release, respectively. Panel B is adapted from Sellam et al. [27] with permission, copyright 2010, Springer Nature. (The figure was prepared with Biorender). ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; BMP, bone morphogenetic protein; IL, interleukin; IL-1Ra, IL-1 receptor antagonist; LTB4, leukotriene B4; MMP, matrix metalloproteinase; NO, nitric oxide; OA, osteoarthritis; PGE2, prostaglandin E2; TIMP, tissue inhibitor of metalloproteinase; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor

Fig. 2

Potential therapeutic targets of small molecules with herbal origin in signaling pathways associated with cartilage degeneration. Name of the compounds: (1) polyphenol-rich pomegranate fruit extract, (2) Egb761, (3) polyoxypregnane glycoside, (4) anemonin, (5) hinokitiol, (6) tetrandrine, (7) oxymatrine, (8) polygalacic acid, (9) zingerone, and (10) icariin. As shown above, some of the compounds have multiple signaling targets. (The figure was prepared with Biorender). TNF-α, tumor necrosis factor-α; TNFR1, tumor necrosis factor receptor 1; TRADD, TNF receptor death domain; MAPK, mitogen-activated protein kinase; IL-1β, interleukin-1β; IL-1R, interleukin-1 receptor; IL-1RAcP, interleukin-1 receptor accessory protein; TOLLIP, Toll-interacting protein; NIK, NF-κB inducible kinase; IKKα, IκB kinase α; IKKβ, IκB kinase β; IκB, NF-κB inhibitor; NF-κB, nuclear factor κB; MMPs, matrix metalloproteinases; ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; IL-6, interleukin-6; IL-8, interleukin-8; COX-2, cyclooxygenase-2; ROS, reactive oxygen species; TIMPs, tissue inhibitor of metalloproteinases; Col2a1, collagen 2a1