Genipin Inhibits RANKL-Induced Osteoclast Differentiation Through Proteasome-Mediated Degradation of c-Fos Protein and Suppression of NF-κB Activation

Abstract

Abstract. People over the age of 50 are at risk of osteoporotic fracture, which may lead to increased morbidity and mortality. Osteoclasts are responsible for bone resorption in bonerelated disorders. Genipin is a wellknown geniposide aglycon derived from Gardenia jasminoides, which has long been used in oriental medicine for controlling diverse conditions such as inflammation and infection. We aimed to evaluate the effects of genipin on RANKLinduced osteoclast differen tiation and its mechanism of action. Genipin dosedependently inhibited early stage RANKL induced osteoclast differentiation in bone marrow macrophages (BMMs) during culture. Genipin inhibited RANKLinduced IkB degradation and suppressed the mRNA expression of osteoclastic markers such as NFATc1, TRAP, and OSCAR in RANKLtreated BMMs, but did not affect c-Fos mRNA expression. Interestingly, genipin markedly inhibited cFos protein expression in BMMs, which was reversed in the presence of the proteosome inhibitor MG132. Furthermore, genipin inhibited RANKLmediated osteoclast differentiation, which was also rescued by overexpression of c-Fos and NFATc1 in BMMs. Taken together, our findings indicate that genipin downregulated RANKLinduced osteoclast differentiation through inhibition of cFos protein proteolysis as well as inhibition of IkB degradation. Our findings indicate that genipin could be a useful drug candidate that lacks toxic side effects for the treatment of osteoporosis.

Massive elimination of multinucleated osteoclasts by eupatilin is due to dual inhibition of transcription and cytoskeletal rearrangement

“…Histone deacetylase inhibitors (HDACis) have exerted potent osteogenic potential related to stability of Runx2 by deacetylases (Kim et al, 2011, Jeon et al, 2006). As such there have been a great number of small molecules or natural products that have been shown to affect osteoclastogenesis (Kim et al, 2014a, Kim et al, 2014a, Lee et al, 2014, Kwak et al, 2010). Although the RANKL/RANK axis is the master regulator for osteoclastogenesis, precise underlying mechanisms for contribution of many coupling factors such as SOST, semaphorin, OSCAR, FcR or OC-STAMP to osteoclastogenesis remains to be explored (Honma et al, 2014).…”

Adrenomedullin inhibits osteoclast differentiation through the suppression of receptor activator of nuclear factor‑κB ligand‑induced nuclear factor‑κB activation in glucocorticoid‑induced osteoporosis

“…A previous study revealed that c-Fos is involved in osteoclast differentiation ( 32 , 33 ). Therefore, the present study investigated the c-Fos expression levels in osteoblasts.…”

Identification of Steroidogenic Components Derived From Gardenia jasminoides Ellis Potentially Useful for Treating Postmenopausal Syndrome

“…Additionally, previous studies indicated that GJE and its active components could improve memory and learning ability, and protect the neurons in animals with brain injury (Sheng et al, 2006 ; Chen et al, 2015 ; Zhang et al, 2016 ). Genipin, a major phytoconstituent of GJE, is a candidate for the treatment of osteoporosis (Hoon Lee et al, 2014 ). GJE was also able to attenuate metabolic syndrome with a combination of other herbal drugs in estrogen-deficient rats (Yang et al, 2016 ).…”