The MMP14–caveolin axis and its potential relevance for lipoedema

Lipoedema is associated with widespread adipose tissue expansion, particularly in the proximal extremities. The mechanisms that drive the development of lipoedema are unclear. In this Perspective article, we propose a new model for the pathophysiology of lipoedema. We suggest that lipoedema is an oestrogen-dependent disorder of adipose tissue, which is triggered by a dysfunction of caveolin 1 (CAV1) and subsequent uncoupling of feedback mechanisms between CAV1, the matrix metalloproteinase MMP14 and oestrogen receptors. In addition, reduced CAV1 activity also leads to the activation of ERα and impaired regulation of the lymphatic system through the transcription factor prospero homeobox 1 (PROX1). The resulting upregulation of these factors could effectively explain the main known features of lipoedema, such as adipose hypertrophy, dysfunction of blood and lymphatic vessels, the overall oestrogen dependence and the associated sexual dimorphism, and the mechanical compliance of adipose tissue. Lipoedema is a disorder characterized by the symmetrical accumulation of mechanically compliant adipose tissue in the proximal extremities. This Perspective article proposes a new mechanism for lipoedema, in which dysfunctional caveolin 1 in adipose tissue becomes uncoupled from key feedback loops with matrix metalloproteinase 14, oestrogen receptor and prospero homeobox 1.