Targeting Sirt1, AMPK, Nrf2, CK2 and Soluble Guanylate Cyclase with Nutraceuticals: A Practical Strategy for Preserving Bone Mass

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There is a vast pre-clinical literature suggesting that certain nutraceuticals have the potential
to aid the preservation of bone mass in the context of estrogen withdrawal, glucocorticoid
treatment, chronic inflammation, or aging. In an effort to bring some logical clarity to these findings,
the signaling pathways regulating osteoblast, osteocyte, and osteoclast induction, activity,
and survival are briefly reviewed in the present study. The focus is placed on the following factors:
the mechanisms that induce and activate the RUNX2 transcription factor, a key driver of osteoblast
differentiation and function; the promotion of autophagy and prevention of apoptosis in osteoblasts/
osteoclasts; and the induction and activation of NFATc1, which promotes the expression of
many proteins required for osteoclast-mediated osteolysis. This analysis suggests that the activation
of sirtuin 1 (Sirt1), AMP-activated protein kinase (AMPK), the Nrf2 transcription factor, and
soluble guanylate cyclase (sGC) can be expected to aid the maintenance of bone mass, whereas the
inhibition of the serine kinase CK2 should also be protective in this regard. Fortuitously,
nutraceuticals are available to address each of these targets. Sirt1 activation can be promoted with
ferulic acid, N1-methylnicotinamide, melatonin, nicotinamide riboside, glucosamine, and thymoquinone.
Berberine, such as the drug metformin, is a clinically useful activator of AMPK. Many
agents, including lipoic acid, melatonin, thymoquinone, astaxanthin, and crucifera-derived sulforaphane,
can promote Nrf2 activity. Pharmacological doses of biotin can directly stimulate sGC.
Additionally, certain flavonols, notably quercetin, can inhibit CK2 in high nanomolar concentrations
that may be clinically relevant. Many, though not all, of these agents have shown favorable
effects on bone density and structure in rodent models of bone loss. Complex nutraceutical regimens
providing a selection of these nutraceuticals in clinically meaningful doses may have an
important potential for preserving bone health. Concurrent supplementation with taurine,
N-acetylcysteine, vitamins D and K2, and minerals, including magnesium, zinc, and manganese,
plus a diet naturally high in potassium, may also be helpful in this regard.
Translated title of the contributionTargeting Sirt1, AMPK, Nrf2, CK2 and Soluble Guanylate Cyclase with Nutraceuticals: A Practical Strategy for Preserving Bone Mass
Original languageEnglish
JournalInternational Journal of Molecular Sciences
Issue number4776
StatePublished - 26 Apr 2022

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