Nutraceuticals Useful for Cartilage Preservation May Inhibit SASP via IL-1 Antagonism
Curiously, IL-1 activity appears to play a key role in the cartilage loss associated with osteoarthritis. 18 IL-
1, produced by inflamed synovial cells or in an autocrine manner by chondrocytes themselves, triggers an
inflammatory state in chondrocytes, characterized by NF-kappaB overactivation, that exerts a catabolic
effect on cartilage matrix. A recent essay has posited that several categories of nutraceuticals have the
potential to intervene in IL-1 signaling in chondrocytes, thereby preventing loss of cartilage matrix.19
These nutraceuticals include phycocyanobilin – which has the potential to prevent the activation of
chondrocyte NADPH oxidase, an aspect of IL-1 signaling that aids NF-kappaB activation;20-23
phytochemical phase 2 inducers, which boost cellular expression of glutathione and of a range of
antioxidant enzymes, including heme oxygenase-1 (HO-1);24-28 AMPK activators such as berberine,
which may antagonize NF-kappaB activation via several complementary mechanisms;29 and glucosamine
- which somehow suppresses the pro-inflammatory impact of IL-1 on chondrocytes in cell culture, 30-35
exerts chondroprotective effects in animal models of osteoarthritis,36-38 and – despite controversy
regarding its utility for pain control in clinical osteoarthritis39, 40 - has been found to preserve cartilage in
patients with osteoarthritis of the knee.41, 42 It is intriguing to speculate that such measures might
likewise have potential for blocking or reversing SASP in senescent fibroblasts, and possibly other types
of senescent cells in which IL-1 drives SASP.
The antioxidant impact of phycocyanobilin and of phase 2 inducers may have the potential, not only to
inhibit induction of SASP, but also to block induction of senescence in cells at risk for oxidatively3
mediated DNA damage.43 Indeed, phycocyanobilin appears to mimic the physiological antioxidant
activity of free bilirubin (a key product of HO-1), and it is intriguing that prospective epidemiological
studies have linked elevated baseline serum bilirubin levels with reduced incidence of, or mortality from,
cancer.44, 45 Arguably, this phenomenon might reflect both protection from initiating DNA damage, and
suppression of SASP. Activation of AMPK likewise has been reported to decrease cellular markers for
DNA damage,46 and may have great potential for cancer prevention – as well as amplification of
healthspan.47-51 However, strong AMPK activity, via an activating phosphorylation of p53, has been
found to promote cellular senescence and p16INK4a expression under certain circumstances.52-55
Nonetheless, expression of p16INK4a, while it can evoke cellular senescence, is not in itself sufficient to
induce SASP.56 Hence, nutraceutical AMPK activators such as berberine,57, 58 independent of their impact
on cellular senescence per se, may indeed have potential for control of SASP. Moreover, there is
evidence that AMPK can interfere with IL-6 signaling, at least in hepatocytes. 59
Glucosamine may be of particular interest in this regard, in light to several recent prospective
epidemiological studies which unexpectedly have observed that regular users of this nutraceutical are at
decreased risk for total mortality and for cancers of the lung or colon.24, 60, 61 Although most of the cell
culture studies demonstrating that glucosamine can antagonize IL-1 signaling have employed
supraclinical concentrations of this agent, it is notable that oral glucosamine has been reported to prevent
increases in serum IL-6 in a rabbit model of atherosclerosis associated with inflammatory arthritis.62
Hence, it is not inconceivable that oral glucosamine – which has shown not only chondroprotective, but
also anti-inflammatory effects in rodent models63, 64 – has the potential to intervene in IL-1a-driven
SASP, and that this helps to rationalize the favorable impact of glucosamine usage observed in
epidemiology. This intervention seems likely to reflect O-GlcNAc modification of key signaling
intermediates – the mechanism whereby glucosamine inhibits TNF-a signaling in endothelial and
vascular smooth muscle cells.65, 66 Indeed, in TNF-a-treated smooth muscle cells, O-GlcNAc
modification of the p65 subunit of NF-kappaB has been found to block an activating phosphorylation of
Ser536 required for optimal transcriptional activity.
Rather than expecting any one of these agents to achieve a definitive effect, it might make better sense to
explore combinatorial strategies. For example, phycocyanobilin and phase 2 inducers have the potential
to block oxidative up-regulation of IkappaB kinase activation; berberine, via Sirt1 activation, may remove
an activating acetyl group from p65;67-69 and glucosamine may inhibit an activating phosphorylation of
p65 on Ser536. Even if tolerable and feasible intakes of these agents achieve these effects to only a
limited extent, their combined impact on the transcriptional activity of NF-kappaB might prove to be
clinically important. Indeed, this strategy might prove to be useful, not just with respect to SASP, but the
broad range of disorders in which NF-kappaB-driven inflammation plays a prominent mediating role. (In
therapeutic circumstances, one could consider adding the natural agent salicylic acid - best administered
as its dimer salsalate - which directly inhibits IKK-b.70, 71 It is not as practical for use in primary
prevention, as effective doses induce reversible auditory side effects in a significant minority of
subjects.72)
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