Why KROX20 Isn’t A Miracle Hair Loss Cure

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KROX20, Baldness, And Bad Media

A few weeks ago, a transcription factor called KROX20 hit headlines as a baldness breakthrough. Why? Because researchers published a study showing that when they deleted the KROX20 gene, a mouse’s hair follicles stopped growing.

The study reached major news outlets. And then came the headlines…

• Medical News Today: “Causes of baldness, gray hair identified“
• Time: “Scientists Discover Why Hair Turns Gray And Goes Bald”
• Net Doctor: “Scientists might have discovered the cure for baldness“

So, are these headlines true? Does KROX20 really hold the cure for baldness?

Let’s put it this way. In this world, there are two truths:

1. 99% of news editors are scientifically illiterate. Don’t trust their headlines.
2. KROX20 probably isn’t a hair loss miracle cure.

Despite the media’s hysteria, KROX20 is likely not a hair loss breakthrough. It’s more likely that KROX20 is just one (of hundreds) of transcription factors our bodies need to make a hair follicle. In fact, that’s actually what the original study suggests (but the media sensationalized the story anyway).

But the KROX20-hair loss connection is important. Why? Because KROX20 isn’t just a transcription factor used for hair follicle development. KROX20 also plays a role in inflammation and fibrosis – two conditions closely linked to pattern hair loss. And the more we learn about this gene, the better our chances of understanding if we can use it to target or treat baldness.

That’s what this article is for. By the end, you’ll uncover…

• What is KROX20?
• The KROX20-hair loss connection
• Why mainstream media exaggerates science – especially hair loss research
• The connection between KROX20, fibrosis, inflammation, and hair health
• What we need to know about KROX20 before we can use KROX20 as a hair loss treatment

What Is KROX20?

Simply put, KROX20 is a gene. And when our cells activate the KROX20 gene, they begin to express something called the KROX20 transcription factor.

Transcription factors are proteins which are responsible for one big thing: activating or deactivating the genes inside our cells. In other words, transcription factor proteins help regulate gene expression (which genes our cells turn on or off).

And that’s what the KROX20 transcription factor is. It’s a protein that tells our cells which genes to turn on and off. This is important because when it comes to hair loss, gene expression might be more important than genes. And it turns out the KROX20 gene (and its transcription factor) is critical for making hair.

KROX20 Is Necessary To Make Hair

The KROX20 gene plays an important role in hair development. During early development, the KROX20 transcription factor expresses in the hair bud – and later the hair canal, sebaceous glands, and outer root sheath. In mature hair follicles, KROX20 is expressed in epidermal cells beneath the hair follicle.

Needless to say, this gene is active during and after hair shaft development.

So what happens to our hair if we delete the KROX20 gene? That’s exactly what researchers at the University Of Texas’ Southwestern Medical Center found out.

While studying a disease known as neurofibroma, these researchers incidentally discovered that, in mouse models, if they muted the expression of the KROX20 gene, the mice stopped growing hair.

The takeaway: the KROX20 gene is likely necessary to develop and maintain hair. That’s it.

But that’s not what we read in the media.

Mainstream Media Misinterprets The Entire KROX20 Study

The KROX20 researchers published their study. And to no fault of their own, the media wildly misinterpreted the results. Rather than say what the findings truly were – that KROX20 is critical for hair growth – they instead wrote that researchers might have found the cure to baldness.

So why is this such an egregious claim?

Because the transcription factors involved in hair development might not have anything to do with the transcription factors involved in pattern hair loss.

The Proteins That Help Grow Hair Might Not Be The Same Proteins That Cause Pattern Hair Loss

Protein transcription factors (like KROX20) aren’t just responsible for hair growth. They’re also responsible for differentiating every single cell in our entire bodies.

Remember: despite the fact that our nucleated cells all share the same DNA (genes), many of our cells look and behave differently. Why? Because when a protein transcription factor attaches to a cell, it tells that cell which genes to activate or deactivate, and in doing so, differentiates that cell… turning it into a heart cell, lung cell, skin cell, or even hair follicle cell.

So what is the KROX20 study really saying? It’s saying that these researchers found one single transcription factor (KROX20) that is likely required for hair follicle development. That’s it!

That doesn’t mean that baldness is caused by a lack of the KROX20 transcription factor – as Time and other news sources suggest. Why? Because from what we know, pattern hair loss isn’t caused by our hair follicles magically deciding to turn off. Pattern hair loss is actually a symptom of scarring.

That’s why researchers call pattern baldness a “scarring alopecia.” And scarring is not the opposite of hair follicle development. In other words, what causes our hair to grow – and what causes pattern baldness – are most likely two different things (and two different sets of transcription factors). There might be some overlap, but I can guarantee you that just because we’ve identified one transcription factor necessary for hair development, that doesn’t mean that same transcription factor is exactly what causes pattern hair thinning.

The only way to explain how wrong it is to say that “KROX20 is the cause of baldness” is to use an analogy. So here’s a hypothetical example using eye health.

Example: How Mainstream News Writers Ruin Science

Let’s pretend we’re mainstream news editors, and we just caught wind of a new study on eye development. Say this study shows that in mice, if we delete a certain protein transcription factor, mice stop making eyeball cells. And if we delete this transcription factor before the mice are born, those mice are born without eyes.

As a mainstream news editor, we want to turn this into a story. So we do two things: 1) spin the study so that it’s relevant to humans, and 2) incentivize people to read our article.

But how? It’s simple. First, we relate this “eye” study to a condition humans fear: blindness. Then we ignore the fact that this study has nothing to do with blindness – but rather eye development – and we start writing.

When we’re done, we add a sensationalized headline of which people can’t resist clicking:

“Scientists Discover Why Eyes Go Blurry And Get Blind“

Then we broadcast our article to the world. And since we’re mainstream news, other media outlets read us. They see our article about what “causes” blindness, and then they react by rewriting it and publishing their own. After all, they don’t want their readers spotting a breaking story on the competition’s website. Within a day, hundreds of news sources follow suit.

The end-result? A massive spread of misinformation.

Why Is This Thinking Wrong?

If we used our brains for just a moment, we’d realize that it’s not that this transcription factor causes blindness. It’s merely that this transcription factor is necessary for the development of a mouse’s eye. After all, that’s what the study concluded.

And in reality, blindness is more likely caused by several other things unrelated to eye development… like inflammation, DNA mutations, scarring, or even the development of cataracts. These may or may not have anything to do with the transcription factors that control for eyeball development.

Here’s another example: scientists discover water is necessary for human cell development. So what do the writers at Time extrapolate? Hmm. Maybe a lack of water is responsible for cell death! The headline: “Scientists discover cure for death.”

Except that’s the dumbest thing I’ve ever heard.

And yet that’s the logic Time used to write their KROX20-hair loss article.

Back To KROX20 and Hair Loss…

Time (and other news outlets) read a study which showed that hair development is dependent on the KROX20 gene. Then they decided to ignore the findings, relate the study to a condition which humans fear (hair loss), and slap on a jaw-dropping headline: “Scientists Discover Why Hair Turns Gray And Goes Bald”.

But in order to make that claim, we need to know the following with 100% certainty:

• In humans, balding hair follicles must have lower KROX20 expression than non-balding hair follicles
• In humans, hair miniaturization must be the direct result of lower KROX20 expression
• In humans, it must be that increasing KROX20 expression simultaneously reverses the balding process

The reality? We don’t know if any of the above are true. So we can’t say that KROX20 is a baldness cure. And we absolutely can’t suggest that the same mechanisms responsible for hair follicle development are the same mechanisms responsible for pattern hair loss.

The Media Always Exaggerates Hair Loss Research

Just last month, hair loss headlines screamed that the biotech company Samumed invented a drug to cure baldness and reverse aging. The drug’s mechanism? Targeting WNT pathways.

What’s the real story? Firstly, targeting WNT for hair loss isn’t that novel. It’s been around for years. And WNT-targeting drugs appear to be just mildly effective against hair loss. In fact, those articles didn’t really publish a breakthrough. They simply raised Samumed’s valuation.

In 2012, the same thing happened… only over a “miracle hair loss discovery” known as prostaglandin D2. Despite researchers’ public reservations over PGD2 being a hair loss cure, the media ramped up the story, not the facts. Today, prostaglandin D2 inhibitors for hair loss have been nothing short of a disappointment.

Does This Mean We Should Ignore KROX20?

Not necessarily. It just means that we need to do more research on KROX20 and its connection to hair loss before we start making big claims.

The good news: we’ve done this for you.

The bad news: it’s too early to tell if KROX20 is a good target for hair loss.

Here’s why.

KROX20 & Pattern Hair Loss

The causes of male and female pattern hair loss are multifaceted. But so far, research shows that the following conditions play a critical role in its development:

• Inflammation
• Fibrosis

That means if we want to reverse hair loss, we probably need to target the conditions that precede it. As such, we’re going to evaluate KROX20 in terms of inflammation and fibrosis.

KROX20 & Inflammation

Scalp inflammation and pattern hair loss are closely connected. And while the source inflammation remains mysterious, there’s evidence that chronic scalp inflammation – either from bone growth, mechanical tension, genetic predisposition, or an unidentified factor – contributes to scalp scarring, and that this scarring eventually restricts our hair follicles of blood, oxygen, and nutrients… eventually miniaturizing the follicles and causing pattern baldness.

KROX20 Might Control Inflammation

Studies show that if we delete two transcription factors in mice – EGR2 (also known as KROX20) and EGR3 – in white blood cells, we induce a pro-inflammatory protein signaling cascade (basically, the mice’s bodies become inflamed). The end-result? The mice develop an autoimmune disease so vicious that it kills them.

Another study shows that polymorphisms (gene variations) in KROX20 are associated with susceptibility to systemic lupus erythematosus – an inflammatory autoimmune condition characterized by organ inflammation, rash, and joint pain.

This all suggests that the downregulation of KROX20 might increase inflammation. But is the opposite true? Can we decrease inflammation by increasing KROX20?

Maybe.

This group of researchers showed that EGR2 (KROX20) over-expression may help downregulate certain inflammatory signaling proteins… and even some of the ones related to hair loss (like IL-17, IL-22, and TNF-beta).

Interestingly, there’s also evidence that EGR2 (KROX20) expression occurs in cells that are experiencing inflammation. The suggestion? KROX2 may work through anti-inflammatory mechanisms to promote hair health.

But again, we won’t know for sure without more research.

KROX20 & Fibrosis

Fibrosis is just another term for the development of excess collagen (or scar tissue). And it’s the development of scalp skin scar tissue that likely triggers pattern hair loss.

KROX20: Does It Cause Fibrosis… Or Protect Against It?

It’s unclear. And the only way to explain why is to dive into the relationship between KROX20 and another protein known to stimulate fibrosis: transforming growth factor beta (TGF-beta).

TGF-beta is a signaling protein which encourages fibrosis, and TGF-beta is elevated upregulated in balding scalp skin (unsurprisingly, since balding scalps are ridden with fibrosis).

TGF-beta encourages fibrosis by turning on a group of genes called early growth response (EGR) genes. Together, certain EGR genes (along with TGF-beta) stimulate collagen production… and too much collagen = scar tissue (fibrosis).

TGF-beta activates many EGR genes (ex: EGR-1, EGR-2, and EGR-3). And interestingly, KROX20 is one of these EGR genes! KROX20 is also known as EGR-2.

So, now that we know that TGF-beta encourages fibrosis by activating EGR genes, and that KROX20 is an EGR gene, can we say that KROX20 + TGF-beta = fibrosis?

No. And why not?

Because not all EGR genes encourage fibrosis. In fact, only some do. Others protect against it. And the research suggests that that there’s some sort of balancing act that we don’t fully understasnd between TGF-beta, KROX20, and the other EGR genes to either promote fibrosis… or stop it from forming.

For example: studies show that EGR-1 promotes fibrosis in the skin and lungs.

In contrast, EGR-2 (KROX20) might reduce fibrosis. In fact, EGR2 can decrease collagen production in certain organ fibrotic tumors. Or in other words, EGR2 might fight against fibrosis.

But there’s conflicting data here…

Paradoxically, another study shows that TGF-beta increases EGR2 (KROX20), and that this increased expression of KROX20 triggers fibrosis. In fact, the researchers from that study believe that increased EGR2 may be involved in the pathogenesis of systemic sclerosis – a disease is characterized by widespread organ fibrosis.

The gist: KROX20 can encourage fibrosis or stop fibrosis. It all depends on the organ we’re studying, how much TGF-beta is around, and the expression of other EGR genes.

In other words, we have no idea if KROX20 will encourage or discourage fibrosis in our scalps. So we have no idea if KROX20 protects against, or encourages, pattern hair loss.

In fact, it could very well be that KROX20 helps us grow hair… until inflammation triggers more TGF-beta to express in our scalps, at which point KROX20 + TGF-beta team up form fibrosis and start working against our hair health. The bottom line: we need to do more research!

And here’s where the plot thickens even more…

In Some Cases, Less KROX20 = Thicker Hair

Aside from TGF-beta, there are a bunch of other things that control KROX20 expression. We’re not going to go into details, but here are the proteins / molecules that we know help regulate KROX20 expression:

• Lin28/Let-7 axis
• Wnt/β-catenin
• Bone morphogenetic protein (BMP) signaling

Now, if we believe that more KROX20 = more hair growth, then it’s easy to assume that if we increase the things that turn on KROX20, then by logic, we would also increase KROX20 and thereby encourage hair growth.

But that isn’t always true. Why? Because KROX20 regulators are finicky. And by increasing the things that regulate KROX20 – like Lin28, Wnt, or BMP signaling – that doesn’t always mean that we also increase KROX20. In some cases, just the opposite is true.

On the one hand, mice mutated to express more Lin28a (a KROX20 regulator) grew thicker hair due to a prolonged anagen phase.

On the other hand, mice treated with a BMP signaling antagonist saw a six-fold decrease in KROX20… and paradoxically, bigger anagen hair follicles and an enlarged hair shaft.

What does this all suggest? By increasing (or decreasing) certain regulators of KROX20, we can simultaneously increase (and decrease) KROX20, while at the same time increasing (or decreasing) hair thickness.

In other words, we have no clue what’s going on. And before we start spouting that more KROX20 = more hair, we better do more research.

The Bottom Line On KROX20 & Hair Growth

It’s unclear if a drug that will increase KROX20 expression will encourage or discourage hair growth. The only thing we do know is that if we eliminate the KROX20 gene, mice can’t grow any hair.

That’s it.

What’s Next For KROX20?

Researchers need to demonstrate that increasing KROX20 in humans increases hair growth in those with pattern hair loss. And in order to do that, we need to prove the following:

• Balding human hair follicles must have lower KROX20 expression than non-balding hair follicles
• In humans, hair miniaturization must be the direct result of lower KROX20 expression
• In humans, increasing KROX20 expression must encourage hair recovery in balding regions

After that, researchers should look into KROX20 regulators like Wnt, BMP, or the Let28/Lin-7 axis to regulate KROX20 expression. Another target could be to block proteins that inhibit KROX20.

And finally, scientists should dive into the relationship between zinc and KROX20. Zinc is required for KROX20 expression. Evidence shows that zinc supplementation can improve hair loss – especially in men and women who are zinc deficient.

As always, we won’t know until we do more research. So don’t believe any KROX20 “hair loss cure” claims!