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Enamelin – A regulator of energy homeostasis?

Enamelin is the largest and least abundant of the three secretory calcium-binding phosphoproteins (enamelin, amelogenin and ameloblastin) and represents about 5% of the total proteins in developing enamel. To date, the enamelin gene (Enam) has commonly been considered as a tooth-specific gene expressed by the enamel organ and (at a low level) by odontoblasts. In the present study Helmut Fuchs and colleagues from the Institute of Experimental Genetics at the HelmholtzZentrum Munich analysed two Enamelin mutant mouse lines (abnormal teeth ATE1 and ATE2) which originate from the Munich ENU mutagenesis screen in the systemic screening of the German Mouse Clinic.

Changes in energy, bone and iron metabolism

In the clinical chemistry screen several parameters were significantly changed between the two mutant lines and wild-type controls. The results indicate that energy, bone and iron metabolism is influenced by the Enam mutations in both mutant lines. For example, mean plasma cholesterol values, plasma a-amylase activity and plasma triglyceride concentrations were decreased in mutant mice of both lines compared with the respective controls. Alkaline phosphatase (ALP) activity was increased in mutant animals of both lines. A slight decrease in the plasma triglyceride concentration was observed in ATE1 mutants. The levels of transferrin were lower in female mutants of both lines than in controls, while male ATE1 mutants showed only a slight decrease, and no significant difference in the transferrin level was detected in male ATE2 mice compared with the respective controls.

Differences were also found in the hematology screen with the red blood count, haemoglobin and haematocrit values being lower in the ATE1 mutant compared to control animals. No significant differences in hematological parameters were detected between ATE2-mutant and control animals.

In the dysmorphology screen in both ATE1 and ATE2 lines reduced bone mineral density (BMD), bone mineral content (BMC) and body weight was observed. In ATE1 mutants and female ATE2 mutants body length was decreased. The analysis of a separate cohort of ATE1 mutants revealed in the peripheral quantitative computed tomography (pQCT) reduced bone density and content.

ATE1 and ATE2 mice differed in body mass, with lower values in mutants compared with controls. In body composition parameters, fat mass was significantly decreased and lean mass was significantly increased in both mutant lines. No differences could be detected in response to a 2-day fasting challenge.

In the behavioural analysis only slight differences were detected. Male ATE2 mice showed significantly increased activity while females did not. The increased activity did not correlate with body mass which leads to the assumption that the body mass differences in ATE2 and ATE1 mice are not caused by increased activity and subsequent resulting effects on energy metabolism. In the Modified Hole Board test only female ATE1 mutant mice reared significantly less than control female mice.

Taken together the results from the different screens there are indicators of differences in energy metabolism pathways. Lowered fat mass and elevated lean body mass, as well as changes in clinical chemical parameters, point to changes in energy homeostasis. Further identified differences in the clinical chemical parameters might indicate changes in iron and bone metabolism.

Enamelin function in other diseases

In order to support the findings that Enam is associated with other organ functions the scientists performed a co-citation analysis using String and the Bibliosphere Pathway Edition of the GENOMATIX Software Suite. Enam was matched with 77 disease-related subject headings. The association of Enam with metal metabolism, vitamin D deficiency, calcium disorders, malnutrition, diabetes mellitus, and kidney diseases, as well with as bone and musculoskeletal diseases, suggests that Enam might also play a role in adults in different areas of the body, supporting the pleiotropic effects observed in the mouse mutants in the study. However, the co-citation analysis does not allow discrimination of whether this is a result of direct interaction(s) or of disease-related interactions (secondary effects).

Does enamelin have pleiotropic effects on organs other than teeth? Lessons from a phenotyping screen of two enamelin-mutant mouse lines”, Fuchs et al., Eur J Oral Sci 2012, 120: 269-277