Recent research demonstrates the central role that signaling pathways have in achieving normal adult hair follicle cycling.
Any deviation or alteration from the norm in any of these components, whether in human or mouse, can lead to an absence of hair follicle cycling, resulting in progressive hair loss.
A recent study demonstrated that lack of the Hh signaling pathway in mice lacking the VDR is linked to hair follicle cycling blockage, and targeted stimulation of Hh signaling restores hair follicle cycling in young mice for a limited amount of time.
"The lack or alteration of VDR in both human and mouse leads to an absence of adult hair follicle cycling, with a defect in anagen re-initiation.
"Interestingly, the lack of VDR does not affect embryonic hair development and has a less striking effect on the interfollicular epidermis, which shows the specificity of VDR action in adult hair follicle cycling," says Daniel D. Bikle, M.D., Endocrine Unit, University of California, San Francisco, and San Francisco VA Medical Center.
In a recent study, Dr. Bikle and colleagues set out to identify genes involved in the control of hair follicle cycling whose expression was affected by the lack of VDR in mice.
For eight consecutive days, wild type and VDRKO mice were treated daily with 25 ul of a topical application of Hh agonist at a concentration of 0.06 ug/ul in a solution of 95 percent acetone and 5 percent DMSO.
Immunohistochemistry evaluations were subsequently performed on the treated areas.
Results showed that VDR-deficient mouse hair follicles have a reduced expression of hair-specific markers and an increased expression of epidermal markers (particularly filaggrin), suggesting a transformation toward an epidermal structure.
In the absence of the VDR, the cells that would normally make the hair shaft (hair keratins) differentiated into a different type of cell and started to produce proteins that are more epidermal in nature.
Additionally, VDR-deficient mice showed a reduction in the expression of multiple signaling pathways involved in the control of hair follicle cycling, particularly at the telogen-to-anagen transition.
"We believe that this abnormal differentiation and shift from hair follicle to a hyperproliferating epidermal type of keratinocyte plays a very important role in the development of tumors and malignancies, which we know are more likely to occur in the mouse which lacks the vitamin D receptor, particularly following chemical or UV radiation exposure," Dr. Bikle says.
"This distorted differentiation process not only causes hair loss, but also predisposes to cancer," he adds.
In the hair follicle, the Hh pathway is absolutely critical for normal hair follicle cycling. Through the application of an agonist to Smoothened, which up-regulates the Hh pathway, the researchers were able to restore the hair follicle cycling and hair growth in VDR-deficient mice in which there was hair follicle cycling arrest.
"Although it was only for one cycle, this proves the hypothesis that Hh signaling is critical for that transition from telogen to anagen, because, in fact, it pushed from telogen to anagen under circumstances the hair would not be able to do otherwise," says Arnaud E. Teichert, Ph.D., Endocrine Unit, University of California, San Francisco, and San Francisco VA Medical Center, and co-author of the study.
It remains unclear why the Hh pathway is reduced in the hair follicles of VDR-deficient mice and, conversely, over-expressed in the epidermis.
According to Dr. Teichert, the Hh and Wnt signaling pathways are believed to be the driving force behind the epidermal hyperplasia.
What causes the shift in the lack of VDR and why there is a lack of coordination in the signaling pathways remain the main goals of research, as this may be linked to the fact that these mice become more sensitive to tumor involvement after UV radiation and after chemical exposure.
Ultraviolet radiation is needed to make vitamin D, but it is also known that such radiation causes skin cancer.
Dr. Bikle puts forth a hypothesis that perhaps the role of the VDR and the vitamin D pathway in the epidermis or in the hair follicle has evolved to have this protective action against the development of a malignancy in the skin caused by UV radiation, as the lack of VDR apparently leads to the development of epidermal tumors.
Whether it is the lack of the VDR or the lack of the ability of the skin to make the active metabolite of the vitamin D remains to be answered.
According to Dr. Bikle, the amount of UVB exposure that you need to optimize the production of vitamin D in the skin may not be harmful in terms of carcinogenesis. Furthermore, low doses of UVB may, in fact, protect against tumors, as well as promote resistance against infection, as the innate immune system is activated through vitamin D.
"The VDR clearly is involved in regulating normal epidermal and hair follicle differentiation, and disruption of that leads not only to failure of hair follicle cycling but could predispose the animals to malignancy.
"A better understanding of the intricacies of these pathways may eventually help researchers in finding targeted treatments for hair loss, and, on a much more important scale, the prevention of malignancy and disease that possibly result from the derailment of these mechanisms," Dr. Bikle says.
Disclosures: Drs. Bikle and Teichert report no relevant financial interests.