A fair number of research groups are involved in investigations of the fine details of age-related hair loss. As in most research related to aging, scientists are for the most part much more interested in mapping the chain of change and consequence in cellular biochemistry than in seeking out first causes. The outcome here is that later attempts to build therapies based on new knowledge tend to involve prevention or alteration of downstream consequences of cellular and molecular damage rather than trying to repair or prevent that damage. All other things being equal, this is never going to be the best path forward. For one the consequences of a given form of damage will always be more numerous and more complex than the damage itself: much more effort is involved in chasing down all the loose ends. Secondly messing with the consequences of damage does nothing about the damage itself, which remains to continue causing harm.
During the active phase of the hair growth cycle, stem cell activity sustains an actively dividing population of epithelial cells at the base of the hair follicle called matrix cells. As progeny of the matrix cells move upward from the follicle base (or bulb), they differentiate into a hardened hair shaft, which emerges above the skin surface. Fully differentiated hair shafts consist of dead, but mechanically sound and highly cross-linked, keratin-filled cells. After a period of active hair shaft production, follicles activate an involution program, during which a large portion of epithelial cells die, and the remaining stem cells are reduced to a tight cluster underneath the skin surface. These follicles then remain dormant for some time; however, they can undergo activation and restart active hair shaft production.
The growth, regression, and resting phases together constitute the hair growth cycle, and this cycling can be influenced by a variety of local and systemic signaling factors. Consequently defects in hair cycling can arise from changes in the normal signaling milieu due to disease, aging, or injury. Commonly, in humans, scalp hair follicles enter resting phase prematurely, and hairs shafts become shorter and fall out, resulting in visible baldness. Therefore, identifying new signaling regulators of hair follicle regression will provide a better understanding of the hair loss pathogenesis mechanism and will likely identify novel therapeutic targets.
To test the function of miR-22, we generated a genetic tool to induce miR-22 overexpression in mouse hair follicles, and interestingly, found that increasing miR-22 results in hair loss in mice due to the premature regression of actively growing follicles. Surprisingly, our data reveal that the expression of over 50 distinct keratin genes are markedly reduced by miR-22 and that silencing of keratin-mediated hair shaft assembly by miR-22 is a prerequisite for follicle regression. In the future, our findings are likely to benefit human hair loss research efforts. Androgenic alopecia, where premature regression of scalp hair follicles is induced by increasing androgen levels, is the most common hair loss disorder in humans. Our unpublished data show that two binding sites for an androgen receptor are located in the promoter of both human and mouse miR-22. These findings support the hypothesis that miR-22 functions in the pathogenesis of Androgenic Alopecia, warranting future studies of miR-22 inhibitors as potential anti-hair loss drugs.