AR Accelerates Premature Senescence of Human DP Cells in Association with DNA Damage

[IDW2BB]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828374/


Abstract

The dermal papilla, located in the hair follicle, expresses androgen receptor and plays an important role in hair growth. Androgen/Androgen receptor actions have been implicated in the pathogenesis of androgenetic alopecia, but the exact mechanism is not well known. Recent studies suggest that balding dermal papilla cells exhibit premature senescence, upregulation of p16INK4a, and nuclear expression of DNA damage markers. To investigate whether androgen/AR signaling influences the premature senescence of dermal papilla cells, we first compared frontal scalp dermal papilla cells of androgenetic alopecia patients with matched normal controls and observed that premature senescence is more prominent in the dermal papilla cells of androgenetic alopecia patients. Exposure of androgen induced premature senescence in dermal papilla cells from non-balding frontal and transitional zone of balding scalp follicles but not in beard follicles. Overexpression of the AR promoted androgen-induced premature senescence in association with p16INK4a upregulation, whereas knockdown of the androgen receptor diminished the effects of androgen. An analysis of γ-H2AX expression in response to androgen/androgen receptor signaling suggested that DNA damage contributes to androgen/androgen receptor-accelerated premature senescence. These results define androgen/androgen receptor signaling as an accelerator of premature senescence in dermal papilla cells and suggest that the androgen/androgen receptor-mediated DNA damage-p16INK4a axis is a potential therapeutic target in the treatment of androgenetic alopecia.

Here, we showed a previously unidentified relationship between androgen/AR signaling and induction of premature senescence in association with DNA damage and p16INK4a upregulation in DPCs. Our study highlights the importance of androgen/AR-accelerated premature senescence in DPCs, a process that is thought to reflect irreversible cell growth arrest in the progression of Androgenetic Alopecia. The acceleration of premature senescence of DPCs by androgen/AR signaling may explain the miniaturization of hair follicles shown in Androgenetic Alopecia patients. These results provide novel impacts of androgen/AR signaling in balding DPCs and offer the potential therapeutic targets on combating for Androgenetic Alopecia.

This paper is free access

 

[bboy4]

Skimmed this. Not sure what to make of it. So androgens kill off DPCs through damaged caused by the way of ARs. So? Isn't this just the current dogma? Is the point that p16INK4a is the thing that does the damage? That if we can find a way to repress the upregulation it will prevent DNA damage to the DPC's? Meaning p16INK4a supression is another target down the DHT casscade? Would this really be any more effective than DHT inhibition? How could we supress p16INK4a? Is there a class of drugs anywhere near developed as anti-angrogens to do the job? What's your take on it?

 

[IDW2BB]

Skimmed this. Not sure what to make of it. So androgens kill off DPCs through damaged caused by the way of ARs. So? Isn't this just the current dogma? Is the point that p16INK4a is the thing that does the damage? That if we can find a way to repress the upregulation it will prevent DNA damage to the DPC's? Meaning p16INK4a supression is another target down the DHT casscade? Would this really be any more effective than DHT inhibition? How could we supress p16INK4a? Is there a class of drugs anywhere near developed as anti-angrogens to do the job? What's your take on it?

Still trying to digest this information as a stand alone and as how it fits within the current theories.

The following excerpt of the research paper struck me as an area of further thought (I bolded the part of intrigue):

These results support previous findings that two important DNA damage sensors involved in the phosphorylation of H2AX–the active form of ATM (ataxia-telangiectasia-mutated kinase) and ATR (ATM and Rad3-related)–were detected only in balding DPCs [18]. Although much of this DNA damage can be repaired and the cell can then re-enter the cell cycle, some of the aberrantly enhanced DSBs might destabilize the genome and potentially trigger premature senescence in DPCs. The roles of TOP2B and ORF2 in DNA damage leading to premature senescence of DPCs need further investigation.