Bioinspired bone therapies using naringin: applications and advances

Abstract

The use of natural compounds for treating chronic bone diseases holds remarkable potential. Among these therapeutics, naringin, a flavanone glycoside, represents one of the most promising candidates owing to its multifaceted effect on bone tissues. This review provides an up-to-date overview on naringin applications in the treatment of bone disorders, such as osteoporosis and osteoarthritis, and further highlights its potential for stem cell pro-osteogenic differentiation therapies. A critical perspective on naringin clinical translation is also provided. The topic is discussed in light of recently developed biomaterial-based approaches that potentiate its bioavailability and bioactivity. Overall, the reported pro-osteogenic, antiresorptive and antiadipogenic properties establish this flavanone as an exciting candidate for application in bone tissue engineering and regenerative medicine.

Figure 1

Overview of various conditions in which naringin has been described to display protective / therapeutic effects. For a more general description of the activity of naringin in these conditions, please see reference [21]. ROS – reactive oxygen species. CNS – central nervous system.

Figure 2

Naringin increases the expression of osteogenic markers, leading to an enhanced mineralization. (A) OC immunostaining of rat BM-MSCs after induction with different naringin doses for 6 days, A1 – control, A2 – 1 µg/mL, A3 – 10 µg/mL. (B) RT-PCR gene expression analysis of osteogenic markers after a 14-day treatment of rat BM-MSCs with different naringin doses. Data is represented in mean ± s.d. (n=5). ^ap < 0.05 versus control group; ^bp < 0.05 versus the OIM group; ^cp < 0.01 versus the 1 µg/mL group; ^dp < 0.01 versus the 10 µg/mL. (C) Alizarin Red S staining of calcium deposits formed in rat BM-MSCs after incubation with various doses of naringin (1, 10 and 50 µg/mL) for 21 days. (D) RT-PCR gene expression analysis of osteogenic markers after a 7-day treatment of human BM-MSCs with different naringin doses. Data represented in mean ± s.d. (n=6). *p < 0.05 and **p < 0.01 compared with the control group (n=6). (E) ALP staining of human BM-MSCs 7 days after drug administration. Adapted from references [25,29] with permission from Elsevier. Reference [26] adapted under a Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/).

Figure 3

Naringin effectively inhibits bone resorption in vitro. (A) Representative scanning electron microscopy (SEM) micrographs of bone resorption pits induced by osteoclast-like cells in bovine bone slices after incubation with different naringin doses (0, 0.5 and 1 mM) for 24 h. (B) Total resorption pit areas of each treatment group as measured under SEM. (C) Microscopic view of TRAP-stained osteoclasts in calvarial bone cultures treated with different doses of naringin for 10 days. (D) Number of TRAP-stained osteoclast cells treated with different doses of naringin for 1, 3,7 and 10 days. *p < 0.05, **p < 0.01, ***p < 0.001. All data above is represented in mean ± s.d. (n=3). Adapted from reference [30] with permission Wiley. Adapted from reference [34] under a Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/).

Figure 4

Pro-osteogenic and pro-angiogenic protective activities of naringin in vivo. (A) 3D reconstruction of trabecular microarchitecture within the distal femoral metaphyseal region in Sham, ovariectomized (OVX), naringin (NG) or exercise (EX) monotherapy or combination regimen groups. (B1) Optimal naringin-induced osteogenic gene (ALP, RUNX2, Col I) expression at 5 mg/kg (n=5). *p < 0.05; **p < 0.01; ***p <0.001 compared to control group. (B2, B3) Naringin-induced (5 mg/kg) increase in ALP activity and osteoblastic cell proliferation. Data represented in mean ± SEM (n=5 and n=3, respectively). #p < 0.05; ##p < 0.01 compared with the OVX group. (C) Naringin markedly inhibited (100 mg/kg) the OVX-induced reduction in bone marrow microvessels (black arrows). Adapted from reference [37] under a Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/). Adapted from reference [38] under a CC-BY-NC license. The final, published version of this article is available at http://www.karger.com/?doi= 10.1159/000430319. Adapted from reference [39] under a CC BY-NC-ND 4.0 International license.

Figure 5

Naringin therapeutic activity in disuse osteoporosis induced by unilateral sciatic neurectomy (USN). (A) Representative 3D images showing the trabecular microarchitecture in the distal femoral metaphysis of each group. (B) Immunohistochemical staining of OC and osteoclasts (TRAP⁺) in the distal femoral metaphysis, as well as histomorphometric analysis of naringin-prevented deterioration of the ipsilateral femurs due to immobilization. Adapted from reference [49] under a Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/).