Proteoglycans

Proteoglycans

Proteoglycans

Proteoglycans are macromolecules composed of a core protein covalently attached to one or more chains of glycosaminoglycans through O- (serine/threonine) or N- (asparagine) bonds.

Glycosaminoglycans (mucopolysaccharides) are long unbranched polysaccharides containing a repeating disaccharide unit. In addition to the ECM (Extracellular Matrix), proteoglycans are abundant in intracellular matrices, cell membranes, and pericellular membranes (the basement membrane zone). Proteoglycans are physiologically active molecules that regulate cellular processes, primarily modifying many signaling pathways. They regulate cell growth, adhesion and migration, collagen fibrillogenesis, immune function, and tissue repair. Any structural distortion or imbalance in the production and degradation of proteoglycans can lead to disorders such as disturbing hair growth.

https://biologywise.com/structure-function-of-proteoglycans

Proteoglycans inside the hair follicle

Hair follicles express a characteristic composition of proteoglycans, contrasting with the surrounding skin environment. The distribution of these specialized molecules changes throughout the hair growth cycle. In the anagen phase of the hair follicle, there are classes of proteoglycans:

1.Lecticans or hyalectans:

  • Versican,
  • Aggrecan

2. Small leucine-rich proteoglycans:

  • Decorin
  • Biglycan

3. Basal membrane proteoglycans:

  • Perlecan
  • Bamacan

4. Membrane-bound proteoglycans:

  • Syndecan- 1

Decades of research have revealed the molecular details of the cyclic redistribution of proteoglycans in the hair follicle. For example, the expression of versican and decorin entirely correlates with the growth activity of the hair follicle. An over 5-fold increase in decorin mRNA during the transition from medium to late anagen (hair growth phase) has been demonstrated.

Functional roles of proteoglycans in the hair growth cycle

After embryonic production, the hair follicle passes between two distinct stages, active and dormant. This process is based on a homeostatic balance between multiple signaling pathways, receptors, growth modulators, transcription factors, circadian molecular clock genes, cytokines, peptides, hormones, and prostaglandins. When this balance is disturbed, there is a shift from one stage to another. By changing a sufficient number of parameters, each hair follicle can be stimulated to enter or remain in one of the two stages.

Proteoglycans are a major component of the ECM microenvironment with direct and indirect contributions to cell signaling and independent roles in the hair growth cycle.

Anagen is a period of hair follicle regeneration induced by the activation of various growth factors, nerve mediators, and metabolic pathways, in which epithelial-mesenchymal interaction is of major importance. The keratinocytes proliferate and differentiate to generate a new hair shaft. Dermal Papilla (DP) fibroblasts initiate anagen by secreting inducers such as Wnt, sonic hedgehog, bone morphogenetic proteins, and fibroblast growth factors (FGFs); this activity is closely dependent on the presence of a proteoglycan-rich microenvironment and will be quickly lost if DP cells are separated from the ECM. Proteoglycans can regulate the expression of growth factors and other anagen inducers.

Wadstein J., Thom E., Gadzhigoroeva A., Integral Roles of Specific Proteoglycans in Hair Growth and Hair Loss: Mechanisms behind the Bioactivity of Proteoglycan Replacement Therapy with Nourkrin® with Marilex® in Pattern Hair Loss and Telogen Effluvium; 2020.

Examples:

  • Lecticans – contain epidermal growth factor-like repeats, and EGF receptor signaling is essential to initiate the hair follicle cycle.
  • Versican – the level of its expression is significantly correlated with the ability of hair papilla cells to induce hair growth. Expression of versican can restore the hair inductance of inactive mesenchymal cells.
  • Decorin – regulates cell death and the synthesis of matrix components. Decorin is a strong anagen inducer. Studies have shown that the supply of decorin during telogen resulted in premature onset of anagen.
  • Syndecan – stimulates pro-angiogenic signaling and is also involved in the Wnt signaling pathway, essential for hair formation.
  • Perlecan – promotes mitogenesis and angiogenesis by activating the FGF-2 and FGF-7 receptors.

Proteoglycans play a key role during anagen – they support cell migration and intercellular interaction. Proteoglycans increase the stability of collagen fibers and protect them against proteolytic cleavage. Versican increases the expression of adhesion proteins, which facilitates the adhesion of cells to the ECM. Decorin binds to several types of collagen and fibronectin, contributing to the lateral growth of fibers and maintaining the integrity of the ECM. The decorin analog biglycan has been documented to act as a reservoir for the Wnt protein and regulate the Wnt / β-catenin pathway, a key cascade in hair follicle differentiation and cyclic growth.

The anti-apoptotic properties of proteoglycans play an essential role in maintaining anagen homeostasis. Decorin shows the strongest apoptosis-inhibiting properties. Proteoglycans are essential for hair follicle stem cells’ proper functioning and survival. The extracellular matrix in the bulge areas, where hair stem cells are located, contains specific growth factor receptors and large amounts of versican. The extracellular matrix in this hair follicle region regulates cell migration and proliferation by binding to various components such as hyaluronic acid, type I collagen, tenascin-R, fibrillin-1, fibronectin chemokines.

Proteoglycans, including syndecans, provide the necessary support in maintaining the pluripotency of human stem cells. Pluripotent cells can differentiate into all the cells of the germinal layers, except for trophoblast cells, which form the placenta at later stages of development.

The immune response

The immune response is crucial for the induction and maintenance of the anagen phase, and disturbances in this process can lead to disorders, as is seen in, for example, alopecia areata (AA). The immunoprotective function of proteoglycans is realized by providing a barrier to the movement of the immune system cells. Perlecan functions as a “border patrol” that keeps different regions of complex tissues separate from each other. Under stress and tissue damage conditions, some proteoglycans, such as biglycan, act as ligands and signaling molecules of Toll-like receptors, while under normal conditions, their presence is essential to control inflammatory responses. More recent studies have demonstrated the role of biglycan in regulating the balance of IL-1β synthesis. Biglycan is the switch between inflammation and autophagy, which determines the chronicity or resolution of the inflammatory response.

Androgenetic alopecia (AA)

The Wnt / β-catenin signaling pathway is blocked by activation of androgen receptors and enhanced by specific proteoglycans. Proteoglycans create a specialized environment around fibroblasts that regulates and manages nearly all autocrine and paracrine signals sent to epithelial precursor cells; Their disturbed metabolism, especially in the dermal papilla area (DP), influences the hair follicle cycles. A possible mediator of the sex hormone-induced DP dysfunction in androgenetic alopecia may be a decrease in the ability of cells to synthesize proteoglycans.

Telogen effluvium (TE)

Postpartum hormone fluctuation causes synchronized endings of the anagen phase in a significant number of scalp hair follicles, causing excessive hair loss several months postpartum. In vivo studies have shown that radical hormonal fluctuations during and after pregnancy can significantly affect tissue proteoglycan homeostasis. Considering this, increasing the concentration of proteoglycans in hair follicles and reactivating dormant follicle cells is a promising target for the prevention and TE treatment.

Hair loss and oral proteoglycan replacement therapy

There is clinical evidence of the efficacy of this new therapy, now known as oral proteoglycan replacement therapy (PRT), using Nourkrin® from Marilex® (manufactured by Pharma Medico Aps, Aarhus, Denmark). The evidence is promising in both men and women for:

  • androgenic alopecia,
  • telogen effluvium,
  • excessive hair loss after bariatric surgery,
  • postpartum hair loss
  • excessive hair loss caused by metabolic syndromes
  • hair loss from stress
  • post Covid – 19 hair loss
  • maintaining the effects of the transplant or other anti-hair loss treatments

Nourkrin® with Marilex® can counteract the effects of sex hormones at a lower level than the receptor. Supplementation may break the vicious cycle of extracellular matrix deficiency, leading to cell dysfunction, which results in hair follicle atrophy and miniaturization. This theory explains the clinical efficacy of Nourkrin® in improving hair growth in both men and women with androgenetic alopecia.

Nourkrin® with Marilex® is currently the only form of proteoglycan-based therapy available to treat common hair growth disorders. It combines enzymatically extracted, marine-derived proteoglycans rich in lecticans and leucine-rich proteoglycans (Marilex®). The safety and effectiveness of this form of treatment have been documented in several clinical trials with men and women. According to the publication, the first signs of effectiveness were detectable after 60 days of treatment (immediate effect). On the other hand, the continuation of the therapy for a total of 6 to 12 months resulted in a significant objective improvement in scalp hair density, hair growth rate, and hair loss reduction (delayed effect). In vivo pharmacokinetic evaluations have shown adequate gastrointestinal bioavailability for marine proteoglycans, indicating that peripheral organs such as the hair follicle are affected by oral proteoglycan supplementation. Proteoglycans and some glycosaminoglycans are absorbed intact through endocytosis, mainly in the small intestine, and this process can be enhanced by repeated dosing.

Remember! Proteoglycan therapy will be effective only in the case of non-scarring alopecia. If some diseases have successfully damaged the hair follicles, or hair follicles have atrophied as a result of the advanced process of androgenic alopecia, then no therapy will restore hair growth.

If you are struggling with excessive hair loss and want to strengthen the effect of the therapy, I invite you to a free consultation about proteoglycan therapy.

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