Vis Medicatrix Naturae

Carrie Decker, ND

As medical research continues to grow, so too does our understanding of the extracellular matrix (ECM) and its dynamic and systemic effects. Once thought to be only a backdrop to the activities of the cells found within it, we now know the ECM has complex means of interacting with the rest of the body, much like adipose tissue.¹ Molecules within the ECM, such as collagen, elastin, and proteoglycans, interact with the cells, influencing cellular signaling,2^,3 cellular differentiation,⁴and even immune system function.⁵

Two families of molecules critical to the structure and function of the ECM are collagen and proteoglycans.6^,7 Collagen provides a structural backbone to the ECM,⁸ while proteoglycans interact with collagen and, as highly hydrophilic molecules, retain water within the ECM. In cartilage, type II collagen is the primary structural backbone of the ECM, with many large proteoglycans – known as aggrecans – interacting with the collagen fibril network and hyaluronic acid.^9,10These aggrecans contain covalently-bound chondroitin sulfate and keratan sulfate chains, collectively known as glycosaminoglycans. In the skin, type I collagen prevails, with type III collagen also being a significant fraction.¹¹ As with cartilage, the proteoglycans found in the skin structurally interact with collagen and affect the skin’s functional properties and structural integrity, in part by retaining moisture within the tissue.¹²

With aging, functional changes in the ECM occur in both cartilage and skin. Chondrocytes have minimal ability to replicate, and their ability to synthesize collagen and proteoglycans declines with age.¹³Similarly, in the skin the number of fibroblasts, as well as their ability to produce these molecules, declines dramatically with age: by age 80, their capacity is only 10-25% of that of fibroblasts sourced from fetal human skin, while the quantity of fibroblasts decreases significantly as well.^14,15

Proteoglycans: Bone Broth of the Future

Collagen has long been used as an oral supplement for its joint- and skin-supportive properties. Numerous scientific studies exist, with collective findings suggesting that oral collagen supplementation supports tissue regeneration and reduces joint pain, bone density loss, and skin aging.¹⁶ Although collagen as a supplement has considerable evidence for its use, proteoglycans are fast receiving interest, given the array of clinical studies showing their benefits. Until recently, techniques did not exist for large-scale extraction of proteoglycans in their natural, unaltered state from animal products. However, recent technological developments enable the safe extraction of proteoglycans from otherwise-wasted byproducts of the food chain, such as animal cartilage.¹⁷

Salmon nasal cartilage is one source of proteoglycans that has been highly researched with positive findings in a myriad of settings. Salmon nasal cartilage proteoglycans (SNCPs) have functional domains and an amino acid composition very similar to the primary proteoglycan, aggrecan, that is found in the articular cartilage of mammals.¹⁸

Effects on Immunity, Inflammation & Arthritis

Similar to the immunomodulatory and oral tolerance effects seen with low doses of type II collagen,¹⁹ oral proteoglycan supplementation has been suggested to have anti-inflammatory effects via mechanisms related to immune tolerance.²⁰ In several animal models of autoimmune disease, supplementation with proteoglycans has been shown to induce a regulatory T-cell response and/or to reduce disease progression.

For example, in a mouse model of ulcerative colitis (UC), mice that received water containing SNCPs had a significantly increased survival rate compared to controls.²¹ A subsequent animal UC model investigated the mechanisms via which SNCPs may have this effect, finding that daily oral administration of SNCPs attenuated progression of colitis and suppressed disease-related inflammatory cytokine levels.²² This was shown to be through the enhanced induction of regulatory T-cells via the Foxp3 gene, a master controller of the regulatory T-cell response.²³ A similar response was seen in experimental autoimmune encephalomyelitis, a common mouse model of multiple sclerosis, including reduced symptom severity and enhanced Foxp3 expression in mice treated once daily with oral SNCPs.²⁴ Finally, in a mouse model of rheumatoid arthritis (RA) (collagen-induced RA), daily oral administration of SNCPs significantly attenuated clinical severity and histological changes via reductions in macrophage and neutrophil invasion as well as levels of inflammatory cytokines and chemokines.²⁵

Anti-inflammatory effects with oral proteoglycan therapies have also been seen in other settings. The inflammatory state associated with type 2 diabetes and obesity, induced by high-fat feeding, has been shown to decrease in mice with oral supplementation of SNCPs.²⁶Supplementation with SNCPs reduced the expression of tumor necrosis factor-alpha (TNFα), interleukin (IL)-6, and the proportion of M1 macrophages that contribute to proinflammatory response and the development of insulin resistance.²⁷ Along with these changes, reductions in both fasting insulin levels and glucose-stimulated hyperglycemia were observed in the mice receiving SNCPs.

Mechanistically, some of the benefits of proteoglycans may also be mediated via their effects on the gut flora. Oral supplementation with proteoglycans has been shown to modulate the balance of bacteria in the gut, increasing lactobacilli and other beneficial, immunomodulatory bacteria and decreasing levels of several bacteria associated with disease.²⁸

Although oral proteoglycan therapies have not yet been studied in human conditions of autoimmunity, they have been shown to have anti-inflammatory effects in clinical studies of osteoarthritis, another condition with inflammation as an underlying factor.29^–31 Multiple randomized, placebo-controlled studies have investigated the impact of proteoglycans in individuals with discomfort of the knee, finding that a very low dose of 5-10 mg significantly improves scores related to joint mobility and pain.^20,32 At a dosage of 5 mg daily, a trend of reduction in high-sensitivity C-reactive protein (hs-CRP) levels was also seen, paralleling the improvements in Visual Analogue Scale (VAS) comprehensive scores. Significantly reduced collagen breakdown was also seen clinically at a dosage of 10 mg daily.³³

Proteoglycans & Skin Aging

The impact of SNCPs on skin health has been assessed in cellular, animal, and human studies. With aging, the composition of proteoglycans in the skin dramatically shifts, leading to diminished hydration, a loss of skin viscoelasticity, and altered wound healing.^34-36 Although important to many of us cosmetically, these changes also contribute to non-healing pressure sores (also known as bed sores or pressure ulcers),³⁷ infections,³⁸ and related complications in the aging population.

In fibroblast monolayer studies, the introduction of a solution containing SNCPs was shown to stimulate cell migration and proliferation.³⁹ In a subsequent animal model, compared to controls, topical application of SNCPs was shown to accelerate the closure of 2 types of wounds, one being infected and the other not, with an increase in transforming growth factor-beta (TGFβ) (which promotes re-epithelialization).⁴⁰ Additionally, application of SNCPs modulated the immune and inflammatory responses and decreased bacterial counts in the infected wounds. Animal studies suggest SNCPs also may protect the skin from the damage caused by the ultraviolet (UV) rays of the sun. In animals exposed to UV-B light, those treated with SNCPs experienced a reduction in erythema, transepidermal water loss, inflammatory cytokine levels, and improved skin hydration compared to controls after 4 and 7 weeks of repeated UV-B exposure.⁴¹

In human clinical studies, improvements in skin appearance and tissue quality have also been seen in subjects taking low does of oral proteoglycans. In a randomized, double-blind, placebo-controlled study of healthy individuals with a mean age of 39 to 40 years old, 5 mg of proteoglycans taken daily for a period of 2 weeks significantly increased skin viscoelasticity, recovery after deformation, and skin hydration (as evaluated by skin conductance), and decreased skin looseness and roughness (as evaluated by skin micrographs).⁴² Improvements were also evident visually, with a significant decrease in wrinkles, conspicuous facial pores, and blotches in the individuals taking proteoglycans. Given that cellular turnover in the skin takes approximately 28 days, one would expect benefits to be even more dramatic after a longer period of use.

Conclusion

Although the changes with aging will never cease to challenge our health in numerous ways, the positive findings from using minimally invasive interventions such as proteoglycans offer hope to those struggling with age-related joint and skin changes. As research surrounding this newly available therapy advances, there likely will be additional studies in settings of autoimmune disease that also may pique further interest. Additionally, as we further understand the role the extracellular matrix plays in other facets of health and disease,⁴³ research investigating the impact of proteoglycans on other aspects of health may soon follow.

References:

Carrie Decker, ND, graduated with honors from the National College of Natural Medicine (now the National University of Natural Medicine) in Portland, OR. Prior to becoming a naturopathic physician, Dr Decker was an engineer and obtained graduate degrees in biomedical and mechanical engineering from the University of Wisconsin-Madison and University of Illinois at Urbana-Champaign, respectively. She continues to enjoy academic research and writing and uses these skills to support integrative medicine education as a writer and contributor to various resources. Dr Decker supports Allergy Research Group as a member of their education and product development team.