Reasons why PTGDS involvement in Androgenetic Alopecia makes sense
All the above is good evidence for the importance of PGD2 in the pathogenesis of Androgenetic Alopecia. The next question is the exact degree of importance. Is PGD2 the dominant agent which is downstream of testosterone and inhibits hair growth? Or is it one of many agents and itself only a minor contributor to Androgenetic Alopecia. The following observations support that PGD2 might be a dominant player, though clearly more work is required (see below).
1. Prostaglandins are already known to modulate hair function.
a. Prostaglandins have already been shown to be important in hair follicle function(7), and
even are clinically useful. The best examples are analogues of PGF2a which have been shown in people to increase hair growth. In many ways reminiscent of the discovery of minoxidil, they were not rationally discovered but do give investigators a clue that the pathways which normally control hair lengthening involve prostaglandins. Also, mice overexpressing the COX2 enzyme develop alopecia(38, 39), though mice generally do not show Androgenetic Alopecia. Therefore the discovery of PTGDS on an unbiased screen is consistent with the above.
2. Prostaglandins often have opposing functions.
a. Prostaglandins typically control bodily functions in a “yin and yang†manner where they
have opposing functions(30). This explains the observation that despite the involvement of prostaglandins in a multitude of organ systems, COX inhibitors like aspirin typically have very restricted clinical effects— because they will inhibit both system activators and system inhibitors with a net negligible effect. For example in the case of bronchial muscle tone, PGD2 increases contraction while PGE2 increases relaxation. In the case of hair, it is known that PGE2 and PGF2a stimulate hair growth, while PGD2 inhibits hair growth(9, 10, 40). This discovery therefore fits current models of prostaglandin function.
3. PTGDS is hormonally responsive in other systems
a. PTGDS is present in seminal fluid and epididymis. PTGDS expression has been shown to
decrease with castration and increase after androgen reintroduction(41-43). But PGDS is also estrogen responsive in some systems(44). Finally, although PGD2 has not been tested, PGE2 has been shown to induce male mating behavior circuits in the developing brain(45). Given low androgen receptor levels in keratinocytes(46-49), an effect of androgens on PTGDS expression might be indirect. Therefore it is clear hormones frequently modulate prostaglandin levels which would be consistent with their role in Androgenetic Alopecia.
4. PGD2 receptors are in the outer root sheath of the hair follicle.
a. Early reports are consistent with receptor’s localization within among other areas to the
upper and lower outer root sheath region as well as the dermal papilla (21). Therefore the location of receptors is appropriate to imagine a functional importance for hair follicle activity.
5. PGD2 might explain sebaceous hyperplasia in Androgenetic Alopecia
a. Although controversial, PGD2 and its non-enzymatic break down product 15-deoxy-
delta 12,14-prostagladin J2 are published as ligands for PPARgamma(50, 51). PPARgamma is a known master transcription factor for adipose development and also supports sebaceous gland function(52). Therefore it is tempting to consider that the high levels of PGD2 might explain the dramatic increase in sebaceous gland size in Androgenetic Alopecia. Whether the sebaceous gland hyperactivity is just a byproduct of Androgenetic Alopecia pathogenesis, or instead actively promotes alopecia is not fully known and also requires more study.
6. Lipid based pathways are underexplored area of biology
a. Given that lipid biology is comparatively understudied to genes and proteins, it is
possible that it has been overlooked in this very common condition.
7. Minoxidil has effects on prostaglandins
a. In early literature on the mechanism of minoxidil’s effect on reducing blood pressure, it was noted that it has the capacity to increase PGE2, which has been shown to be reduced in Androgenetic Alopecia(53-55). Although not proven, minoxidil’s effects on prostaglandins would be consistent with their aberrant regulation in Androgenetic Alopecia.
8. Recent genetic analysis show associations of Androgenetic Alopecia with GPR44 which approach significance.
a. Although not fully statistically significant, a recent GWAS dataset of Androgenetic Alopecia was analyzed
for associations to the PGD2 pathway(56). GPR44 was nominally significant (p=0.03).
The authors point out that larger sample sets might improve this association.
9. Classic developmental pathways controlling hair morphogenesis likely will not be directly
affected in a disease like Androgenetic Alopecia.
a. Many potent developmental pathways have been shown to modulate hair follicle
function (wnts, shh for example(57)). However, if these pathways were directly modulated by androgens in Androgenetic Alopecia for example, the phenotype of Androgenetic Alopecia would likely be considerably broader. A more plausible model is that Androgenetic Alopecia will modulate upstream pathways which only indirectly modulate these very powerful developmental pathways. Prostaglandins might be that modulator factor.
Outstanding questions the field must solve
1. Replication by other groups.
a. Given the novelty of these findings, it will be important that other groups independently
assess PGD2 using highly accurate methods such as mass spectrometry. If PGD2 is elevated in bald scalp in those studies, other questions include: Are the elevations of PGD2 heterogenous within areas of the scalp? What are the PGD2 levels in early versus late Androgenetic Alopecia disease?
2. Do prostaglandins simply modulate hair growth rates or actually hair cycling?
a. Most hair biologists believe the final length of a hair shaft is determined mostly on the
time spent in the anagen growth phase versus the other phases of the hair cycle. Interestingly, published data with prostaglandins are more consistent with modulations on hair follicle growth rate and not cycling. If the case, this is an underappreciated mechanism of regulating hair growth. However, detailed studies to test this have not been performed.
3. More in depth descriptions of PGD2 in hair biology
a. There are a host of important questions to answer. How does the prostaglandin D2
pathway change during the human hair cycle? Although much of the previous work on the fluctuations in the PGD2 pathway during the hair cycle have been done on mouse, more work investigating human hair cycle fluctuations are important. Similarly, is PGD2 not involved in senile alopecia? Does PGD2 induce recruitment of inflammatory infiltrates seen in Androgenetic Alopecia; can fibrosis be recapitulated after PGD2 exposure?
4. Create mouse genetic models of increased PGD2 in the skin.
a. Although a mouse with elevations of PGD2 demonstrates alopecia (COX2 mouse), it also
has increases in other prostaglandin species as well. Does a mouse with unique
elevations of PGD2 also demonstrate alopecia?
5. Demonstration that in skin PTGDS is hormonally responsive.
a. While PTGDS is hormonally responsive in many tissues(41-43), it has not been demonstrated in skin cells such as keratinocytes, fibroblasts or sebocytes.
6. Do women have similar increases in PGD2?
a. All the original work on PGD2 in alopecia was done on males, but do females with
patterned alopecia show similar changes?
7. Visualization of where PGD2 is located.
a. Methods exist which combine mass spectrometry with 2-D samples to identify localization of lipid species(58). Using these techniques, in what compartment is PGD2 elevated?
8. Does PGD2 inhibition help Androgenetic Alopecia? While multiple GPR44 inhibitors are marketed, their individual selectivity for GPR44 is quite variable. If optimum GPR44 inhibition occurs, can hair miniaturization be reversed?
a.
To patients with Androgenetic Alopecia this is the only question of concern. Many groups are actively searching for GPR44 inhibitors already. However, there are important issues in designing a therapy which might be effective for Androgenetic Alopecia. One issue is timing: must inhibition of the pathway being in puberty when circulating androgens increase to prevent any increases of PGD2? Is the inhibition of PGD2 on hair growth reversible? Although GPR44 therapies are being designed for allergic diseases, their usefulness in Androgenetic Alopecia might be compromised if the necessary schedule and delivery are different for inhibiting GPR44 in the hair follicle. The larger the number of candidate compounds to test for GPR44 inhibition in the hair follicle, the greater likelihood of success. If existing candidates for GPR44 inhibition fail to prove useful, the search for new candidates will be more pertinent. Given the likely important locus of expression of GPR44 in keratinocytes, the development of keratinocyte reporter cell lines for GPR44 activity would allow for large scale screening of compounds to inhibit this pathway and provide a pipeline for potential small molecule candidates.
If appropriate GPR44 inhibition can be achieved, the most important of all the above questions will address the reversibility of Androgenetic Alopecia in human subjects.
