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A New Look at Cellulite, Part 1

By: Peter T. Pugliese, MD
Posted: June 26, 2008, from the July 2008 issue of Skin Inc. magazine.

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Part of the magic of birth is the mystery of conception. Essential to a successful pregnancy is a viable implant of the fertilized egg. To achieve this perfect state, the body will prepare a new endometrium each month for a possible pregnancy. In her child-bearing lifetime, a women may have 400 or more menstrual cycles. It is the enzymes that build up and destroy the endometrium each month that account for the existence of cellulite in women. An understanding of this process requires a familiarity with the biology of the menstrual cycle, so a brief review is in order.

The normal menstrual cycle. The uterus is a muscular structure that is lined with a highly vascular and proliferative tissue called the endometriumd. Each month, under the hormonal influence of follicle-stimulating hormones (FSH), the ovary will begin to ripen and extrude an egg (the ovum). This same hormone will influence the endometrium to start a new cycle of growth. All of this process starts in the hypothalamus, where the specific stimulating hormones originate to direct the pituitary gland to produce the FSH and the luteinizing hormones (LH) needed to prepare the endometrium by directing the ovaries to secrete the female hormones, estrogen and progesterone. Figure 3 illustrates the process in detail. At the end of this phase, the endometrium must be shed if no pregnancy has occurred, and this is the very process that also initiates the condition known as cellulite.

Matrix metalloproteinases (MMPs). When pregnancy does not occur, the sex hormones, estrogen and progesterone fall to very low levels. This initiates a series of events that removes the endometrium by a collagenolytic process called shedding. In this process, specific enzymes, known as matrix metalloproteinases (MMPs) cleave to the collagen fibers and break them down into peptides and amino acids, to be recycled in the metabolic pool. These same enzymes are also responsible for the degradation of other type I collagen structures elsewhere in the body, particularly in the thighs and buttocks—the cellulite area.

This article cannot focus on MMPs in a comprehensive manner, but the basics must be covered in order to allow for a full appreciation of the real nature of cellulite. The four classes of MMPs are the collagenases, gelatinases, stromelysins and membrane-type enzymes (MT-MMPs). All these enzymes share certain characteristics: 1. They all contain zinc metal at the active site; 2. They are synthetized in an inactive form, known as a preproenzyme, and secreted into the extracellular matrix (ECM); 3. They are activated in the ECM; 4. They recognize and cleave the ECM components; and 5. They are inhibited by both serum-borne and extracellular-specific MMP inhibitors. Following are a few of the MMPs and their substrates.

  • The collagenases are grouped as MMP-1, MMP-8 and MMP-13. These MMPs can cleave many types of collagen, including types I, II, III, V and XI, which are fibrillare. When these collagen types are cleaved, they become more soluble and form gelatin.
  • The gelatinases, MMP-2 and MMP-9, can now take over and attack type IV collagen—the basement membrane of the epidermis—fibronectin and laminin.
  • The MMP-3, MMP-7, MMP-10 and MMP-11 attack similar proteins and peptides.
  • The metabolic function of these enzymes is quite diverse, because they not only attack connective tissues, but also can direct cell growth by regulating the amount of growth factor bioavailability.
  • The MT-MMPs appear to have a key role in this regulation, as well as in controlling other MMPs.
  • TIMPs are tissue inhibitors of MMPs. There are four types: TIMP I, TIMP II, TIMP III and TIMP IV.

The menstrual cycle and MMPs

Keep in mind as you read this section that menses occurs each month, and the rise and fall of these enzymes is critical to both ovulation and menstruation. Cellulite is a spin-off process of these enzymes, as are many of the other connective tissue disorders. Ovulation is a major process necessary for an eventual pregnancy. In Figure 3, the process is illustrated and following are the steps.