Proteoglycans as a Critical Facet of a Healthy Extracellular Matrix

Salmon Nasal Cartilage–Derived Proteoglycans Offer Anti-Aging Benefits to Joints and Skin By Dr Carrie Decker ND

We often don’t know what we have until it is gone. Our youthful skin with its healthy glow, the ease with which we jump out of bed to take a morning run: these are things we often do not recognise as important until they start to change.

With osteoarthritis (OA) affecting more than 15% of the population over the age of 30,[1] and leading to the prescription of nonsteroidal anti-inflammatory drugs (NSAIDs) in over 50% of those affected, and opioids in approximately one-third, we can’t deny the impact of this chronic degenerative condition. The medical costs associated with osteoarthritis are also significant: a 2009 survey showed this condition cost insurance companies in the USA over $4,000 per affected person yearly and also contributed to out-of-pocket costs of roughly $1,000 a year.[2] The numbers don’t improve with age: more than 5% of individuals have had a total hip replacement, and 10% a total knee replacement, by age 80.[3]

Although cosmetic skin procedures don’t fall in the realm of necessary medical care, they are still often sought out: over 15.9 million surgical and minimally invasive cosmetic procedures were performed in the U.S. in 2015, a 2% increase from 2014.[4] The skin care industry is booming, with advertisements for skin care supplements, products, and devices pervasive in print, television, and online media. Collagen, once something we only found in homemade bone broths and soups, can now be found in virtually every format, from natural sodas to hand-warming beverages.

Although collagen as a supplement has considerable evidence for its support of the skin and joints,[5] proteoglycans are also critical to the health of the extracellular matrix and are fast receiving interest given the array of clinical studies showing their benefits.

Proteoglycans: Critical for the Health and Integrity of the Extracellular Matrix

Articular cartilage, which covers the ends of the long bones where they come together to form joints, contains high amounts of type II collagen and proteoglycans made by the chondrocytes found within it. Type II collagen is the primary structural backbone of the matrix, with many molecules of aggrecan, a large proteoglycan that contains covalently bound chondroitin sulfate and keratan sulfate chains (collectively known as glycosaminoglycans [GAGs]), interacting with the collagen fibril network and hyaluronic acid through proteins known as link proteins.[6]^,[7],[8] More than 65% of articular cartilage by weight is fluid,[9] largely retained in the cartilage by the hydrophilic nature of the proteoglycans and hyaluronic acid,[10] with only 5% of the cartilage volume being occupied by chondrocytes. Unfortunately, chondrocytes have minimal ability to replicate, and their ability to synthesise cartilage and proteoglycans declines with age, which is one issue that contributes to diminished articular tissue integrity with age.[11]

Proteoglycans are also essential to the health of the skin. Similar to cartilage, proteoglycans affect the skin’s functional properties and structural integrity, in part by retaining moisture in the tissue.[12] With aging and sun exposure, the composition of proteoglycans in the skin dramatically shifts, contributing to different tissue properties, diminished hydration, loss of skin viscoelasticity, and altered wound healing.[13]^,[14],[15]

Cartilage Degeneration in Osteoarthritis and the Impact of Proteoglycans

In addition to chondrocyte senescence, other factors also contribute to the histological changes and eventual degeneration of articular tissue, and the associated symptoms of joint stiffness, pain, and loss of mobility typical of OA. Two phases of OA have been described: a biosynthetic phase, in which the chondrocytes are actively involved in tissue repair, and a degenerative phase that follows, in which matrix synthesis is inhibited and the chondrocytes themselves contribute to the production of enzymes involved in cartilage degradation.[16] Focal lesions from which these changes initiate have also been implicated in the pathogenesis of OA,[17] with increased mechanical forces due to joint instability contributing to cartilage degradation.

In addition to holding moisture in the tissue matrix, proteoglycans help structurally protect the cartilage from deterioration. As OA progresses, however, the proteoglycans are lost from the superficial articular cartilage surface to which the type II collagen runs parallel and the highest tensile forces, due to shear stress, exist. As the body dynamically attempts to remodel and repair the tissue in the early stages of OA, an increase in proteoglycans is seen deeper within the tissue, as if the body is attempting to counteract the surface changes.[18] The concentration of proteoglycans decreases in the later stages of disease,[19] however, with proteoglycan fragments in addition to the enzymes contributing to their degradation being observed in the joint synovial fluid.[20]^,[21] The degradation of aggrecans via a family of enzymes collectively known as aggrecanases has been recognized as a major mechanism contributing to the histopathological changes associated with OA, and medications directed at inhibiting this process are in an ongoing process of investigation.[22]

OA is often accompanied by systemic inflammatory changes, with human studies showing higher levels of high-sensitivity C-reactive protein (hs-CRP) in populations who experience this condition. These changes are seen early in the disease, even after adjustment for age, weight, lifestyle factors, and injury.[23]^,[24] High levels of hs-CRP predict disease progression and are related to disease severity[25]^,[26] and correlated with local tissue changes and inflammatory infiltrates in the synovial membranes and fluid of the involved joint.[27]^,[28] With the inflammation typical of OA as well as rheumatoid arthritis (RA), levels of prostaglandin E2 (PGE2), interleukin (IL)-1, and tumor necrosis factor alpha (TNF-α) also increase and contribute to proteoglycan and cartilage degradation.[29]^{,[30],[31],[32]}

Interestingly, protein fragments (known as link proteins[33]) of proteoglycan aggregates found in cartilage have been observed to stimulate proteoglycan and collagen synthesis in in vitro studies.[34]^,[35] The link protein N-terminal peptide has also been shown to stimulate cartilage regeneration by increasing the proliferation, migration, and chondrogenic differentiation of cartilage stem/progenitor cells.[36] Additionally, link protein N-terminal peptide counteracts degenerative changes induced by IL-1α.[37]

The Dynamic Array of Research Behind Salmon Cartilage–Derived Proteoglycans

Salmon nasal cartilage is one source of proteoglycans that has been highly researched with positive findings in a myriad of settings, including several animal models of autoimmunity,[38]^{,[39],[40],[41]} allergies,[42] infection,[43] wound healing,[44] diet-induced inflammation,[45] and ultraviolet (UV) light–associated skin damage,[46] as well as clinical studies of joint pain,[47] arthritis,[48] and skin aging.[49]

Salmon nasal cartilage primarily contains the proteoglycan aggrecan, which has an amino acid composition and functional domains very similar to the aggrecan found in the articular cartilage of mammals.[50] In cell cultures, salmon nasal cartilage proteoglycans (SNCPs) have been shown to reduce matrix metalloproteinase expression,[51] a primary contributor to cartilage degradation.[52] Early studies performed with SNCPs in macrophages stimulated with heat-killed Escherichia coli suggest these proteoglycans have immunomodulatory and anti-inflammatory effects[53]—treatment with the SNCP solution reduced levels of the pro-inflammatory cytokine TNF-α and nitric oxide synthase (also a contributor to the joint destruction in OA[54]), and increased IL-10.

Clinical Studies with SNCPs.

There is strong clinical data supporting the use of SNCPs for the management of joint pain and as an anti-aging skin strategy. Very low oral doses of proteoglycans, ranging from 5 to 10 mg daily, have evidence in these regards.

In healthy subjects (40 to 75 years of age) complaining of some level of discomfort in the knee joint, 5 mg of SNCPs taken daily led to significant improvements in the Visual Analogue Scale (VAS) comprehensive scores in the proteoglycan group compared to placebo after four weeks, paralleled by a trend of reduction in hs-CRP levels.⁴⁷ In a similar study, healthy subjects with knee discomfort taking 10 mg of SNCPs daily for 12 weeks were found to have significantly improved aggregate Japanese Knee Injury and Osteoarthritis Outcome Score (J-KOOS) scores compared to placebo at weeks four and twelve, and there were also significant intragroup improvements in knee range of motion and pain VAS scores associated with both movement and rest.[55] Analysis of markers of collagen breakdown and synthesis showed significantly reduced collagen degradation and a nonsignificant increase in collagen synthesis in aging individuals with knee joint discomfort taking 10 mg of SNCPs daily for 16 weeks compared to placebo.[56

A combination of type II collagen and SNCPs has also been clinically studied and shown to improve joint discomfort and function at low doses. In healthy subjects experiencing rigidity of the knee, daily supplementation with 50 mg of salmon nasal cartilage, containing 40% undenatured type II collagen and 30% proteoglycans, significantly improved Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and pain VAS scores by four weeks, compared to placebo.⁴⁸

Skin appearance and tissue quality have also been shown to improve with a low daily dose of proteoglycans. Men and women (with a mean age of 39 to 40 years) who took 5 mg of SNCPs daily for only two weeks were found to have significantly increased skin viscoelasticity and recovery after deformation, and decreased skin looseness, compared to placebo.⁴⁹ Additionally, there was a significantly decreased appearance of wrinkles, conspicuous facial pores, and blotches within the SNCP group. Improved skin conductance, signifying improved hydration, and reduced roughness as evaluated by skin micrographs, were also seen in those taking SNCPs. Given that the time for turnover of the cells in the skin is normally more than 28 days,[57] it is possible that these effects may have been even more significant or dramatic after a longer period of time.

As these studies suggest, the health benefits SNCPs may confer extend beyond their importance as a structural element of the extracellular matrix. As we continue to learn more about the signaling that occurs between the extracellular matrix and the immune system[58]^,[59] and the role the extracellular matrix plays in other facets of health and disease,[60] it is likely we will further understand the mechanisms via which proteoglycans may have such a dramatic impact on health.

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