KYMASIN UP Natural Product Inhibits Osteoclastogenesis and Improves Osteoblast Activity by Modulating Src and p38 MAPK

Abstract

The imbalance in osteoblast (OB)-dependent bone formation in favor of osteoclast (OC)-dependent bone resorption is the main cause of loss of tissue mineral mass during bone remodeling leading to osteoporosis conditions. Thus, the suppression of OC activity together with the improvement in the OB activity has been proposed as an effective therapy for maintaining bone mass during aging. We tested the new dietary product, KYMASIN UP containing standardized Withania somnifera, Silybum marianum and Trigonella foenum-graecum herbal extracts or the single extracts in in vitro models mimicking osteoclastogenesis (i.e., RAW 264.7 cells treated with RANKL, receptor activator of nuclear factor kappa-Β ligand) and OB differentiation (i.e., C2C12 myoblasts treated with BMP2, bone morphogenetic protein 2). We found that the dietary product reduces RANKL-dependent TRAP (tartrate-resistant acid phosphatase)-positive cells (i.e., OCs) formation and TRAP activity, and down-regulates osteoclastogenic markers by reducing Src (non-receptor tyrosine kinase) and p38 MAPK (mitogen-activated protein kinase) activation. Withania somnifera appears as the main extract responsible for the anti-osteoclastogenic effect of the product. Moreover, KYMASIN UP maintains a physiological release of the soluble decoy receptor for RANKL, OPG (osteoprotegerin), in osteoporotic conditions and increases calcium mineralization in C2C12-derived OBs. Interestingly, KYMASIN UP induces differentiation in human primary OB-like cells derived from osteoporotic subjects. Based on our results, KYMASIN UP or Withania somnifera-based dietary supplements might be suggested to reverse the age-related functional decline of bone tissue by re-balancing the activity of OBs and OCs, thus improving the quality of life in the elderly and reducing social and health-care costs.

Myrislignan Targets Extracellular Signal-regulated Kinase (ERK) and Modulates Mitochondrial Function to Dampen Osteoclastogenesis and Ovariectomy-i nduced Osteoporosis

“…Afterward, a battery of synergistic genes is upregulated by NFATc1 activation, covering Mmp9, Atp6v0d2, Acp5, Dcstamp, and CTSK, which promotes the formation of mature osteoclasts and bone resorption (34,35,57). When osteoclasts perform a resorption function, MMP-9 is indispensable for the migration and resorption function of mature osteoclasts (9,34,46). While Atp6v0d2 not only regulates H + secretion but also dissolves the crystalline hydroxyapatite and organic matrix (34,62,63).…”

“…The induction of osteoclast differentiation is in connection with the binding of RANK to RANKL (7,10). And then, RANKL/RANK signaling gives rise to the collection of TNF receptor-associated factor 6 (TRAF6) (9), inducing the mobilization of several subsequent pathways, such as mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways (11,21), which are classical pathways related to osteoclast differentiation (10). NFATc1, the critical osteoclastogenesis-controlling master transcription factor, is subsequently initiated to express by RANKL (10).…”

“…Because of the bene cial properties of active metabolites in natural compounds (9), their use in various diseases, such as osteoporosis, is expanding. MRL has extensive pharmacological activities, a natural product derived from nutmeg, an aromatic evergreen tree (32,33).…”

Recent advances of NFATc1 in rheumatoid arthritis-related bone destruction: mechanisms and potential therapeutic targets

“…Wang et al found that Thiaplakortone B (TPB, a natural compound derived from the Great Barrier Reef sponge Plakortis lita) blocked multiple upstream pathways of osteoclast differentiation, including MAPK and NF-κB signaling pathways, which in turn inhibited NFATc1 expression and osteoclast formation (Wang et al 2022d ). Salvadori et al discovered that KYMASIN UP, a new dietary product, inhibited osteoclast formation by reducing p38 MAPK activation, resulting in the downregulation of bone fracture markers (Salvadori et al 2022 ). Qiu et al found that neratinib, a small molecule compound, inhibited the expression of osteoclast-specific genes by inhibiting the MAPK pathway, thereby suppressing osteoclast differentiation as well as cartilage degradation and osteoclast formation (Qiu et al 2022 ).…”