Re-appraising the potential of naringin for natural, novel orthopedic biotherapies

Abstract

Naringin is a naturally occurring flavonoid found in plants of the Citrus genus that has historically been used in traditional Chinese medical regimens for the treatment of osteoporosis. Naringin modulates signaling through numerous molecular pathways critical to musculoskeletal development, cellular differentiation, and inflammation. Administration of naringin increases in vitro expression of bone morphogenetic proteins (BMPs) and activation of the Wnt/β-catenin and extracellular signal-related kinase (Erk) pathways, thereby promoting osteoblastic proliferation and differentiation from stem cell precursors for bone formation. Naringin also inhibits osteoclastogenesis by both modifying RANK/RANKL interactions and inducing apoptosis in osteoclasts in vitro. In addition, naringin acts on the estrogen receptor in bone to mimic the native bone-preserving effects of estrogen, with few systemic side effects on other estrogen-sensitive tissues. The efficacy of naringin therapy in reducing the osteolysis characteristic of common musculoskeletal pathologies such as osteoporosis, degenerative joint disease, and osteomyelitis, as well as inflammatory conditions affecting bone such as diabetes mellitus, has been extensively demonstrated in vitro and in animal models. Naringin thus represents a naturally abundant, cost-efficient agent whose potential for use in novel musculoskeletal biotherapies warrants re-visiting and further exploration through human studies. Here, we review the cellular mechanisms of action that have been elucidated regarding the action of naringin on bone resident cells and the bone microenvironment, in vivo evidence of naringin's osteostimulative and chondroprotective properties in the setting of osteolytic bone disease, and current limitations in the development of naringin-containing translational therapies for common musculoskeletal conditions.

Keywords: diabetes mellitus; naringin; osteoarthritis; osteoclastogenesis; osteomyelitis; osteoporosis.

Figure 1.

In vitro effects of naringin. (a) Naringin has been shown to increase osteoblastogenesis and thus bone anabolism. Naringin increases osteoblastogenesis through upregulating BMP-2, a protein responsible for the differentiation of MSCs down an osteoblastic lineage, directly and by stimulating the Wnt/β-catenin pathway which converges on further upregulation of BMP-2. (b) MSCs grown in the presence of naringin demonstrate increased osteoblastogenesis and decreased adipogenesis. MSCs in the presence of naringin express increased levels of osteoblastic genes such as BMPs and RUNX2 and decreased gene expression of the adipogenic PPARγ. (c) Naringin has been shown to decrease osteoclastogenesis and thus osteolysis in osteoclastic pathologies, such as osteoporosis in menopause and diabetic osteoporosis. Naringin decreases osteoclastogenesis by inhibiting RANK/RANKL interaction by inducing expression of the receptor decoy OPG as well as directly decreasing expression of osteoclastic genes. (d) Physiological levels of estrogen maintain bone stock in females by inducing osteoclast apoptosis and decreasing inflammatory cytokines that are osteoclastogenic; therefore, the loss of estrogen results in osteoporosis due to increased osteoclastogenesis. Through interactions with estrogen receptor α, naringin increases interactions between the death receptor Fas and its ligand FasL which increases osteoclast apoptosis, which tips bone homeostasis from a catabolic to an anabolic state, like endogenous estrogen. Naringin also decreases the inflammatory cytokines IL-1, IL-6, and TNF-α that stimulate osteoclastogenesis. BMP-2, bone morphogenic protein 2; IL, interleukin; MSC, mesenchymal stem cell; OPG, osteoprotegerin; TNF, tumor necrosis factor;

Figure 2.

In vivo effects of naringin. (a) Osteoporosis secondary to the loss of estrogen’s anabolic effects during menopause, the proinflammatory state of diabetes that promotes osteoclastogenesis, or the loss of p-ERK due to glucocorticoid use leads to decreased trabeculae volume, yielding an increased risk of fracture. (b) Naringin prevents osteoporotic bone fractures by increasing the number and thickness of trabeculae. (c) Osteoarticular degenerative conditions such as osteoarthritis, ankylosis spondylitis, and rheumatoid arthritis are characterized by increases in the expression of inflammatory cytokines such as IL-1β, IL-6, and TNF-α, decreases in reactive oxygen species-neutralizing enzymes such as SOD, CAT, and glutathione peroxidase, and increases in cartilage-degrading enzymes, including MMPs and ADAMTS5. (d) Naringin has been shown to be cartilage-protective by decreasing the expression of these inflammatory cytokines, reactive oxygen species, and destructive enzymes. Naringin has also been shown to increase the cartilage-protective effects of IL-4 and T_regs. (e) Osteomyelitis is characterized by the proliferation of bacteria that degrade bone both directly via bacterial products and indirectly by inducing inflammation productive of osteoclastic cytokines. (f) Naringin demonstrates antibacterial effects against common Gram-positive and Gram-negative organisms commonly implicated in the pathogenesis of osteomyelitis. CAT, catalase; IL, interleukin; MMP, matrix metalloproteinase; SOD, superoxide dismutase; TNF, tumor necrosis factor; T_reg, regulatory T-cell;