Glade Report for Glucosamine and chondroitin sulfate

Based on my review of the reliable and credible scientific literature regarding articular cartilage biochemistry and physiology, cartilage degeneration, degenerative joint disease and osteoarthritis, I conclude that there is significant scientific agreement in support of the following health claims:

1. Glucosamine may reduce the risk of osteoarthritis.
2. Chondroitin sulfate may reduce the risk of osteoarthritis.
3. Glucosamine and chondroitin sulfate may reduce the risk of osteoarthritis.
4. Glucosamine may reduce the risk of osteoarthritis-related joint pain, tenderness and swelling.
5. Chondroitin sulfate may reduce the risk of osteoarthritis-related joint pain, tenderness and swelling.
6. Glucosamine and chondroitin sulfate may reduce the risk of osteoarthritis-related joint pain, tenderness and swelling.
7. Glucosamine may reduce the risk of joint degeneration.
8. Chondroitin sulfate may reduce the risk of joint degeneration.
9. Glucosamine and chondroitin sulfate may reduce the risk of joint degeneration. Glucosamine may reduce the risk of cartilage deterioration.
10. Chondroitin sulfate may reduce the risk of cartilage deterioration.
11. Glucosamine and chondroitin sulfate may reduce the risk of cartilage deterioration.


Composition and Physiologic Functions of Articular Cartilage and the Biochemical and Physiologic Roles of D -Glucosamine and the Chondroitin Sulfates

Cartilage is composed of a complex extracellular matrix of collagen and elastic fibers within a hydrated gel of glycosaminoglycans and proteoglycans. This specialized network is stabilized by means of intermolecular and intramolecular cross-links that harness the swelling pressure exerted by the high concentration of negatively charged aggregates. ¹ This accounts for more than 98% of the articular cartilage volume; cellular components constitute the remaining 2%. The interaction of these matrix components imparts the characteristic biomechanical properties of flexibility and resistance to compression. The collagen component of the cartilage matrix is relatively inert, but the other constituents, such as proteoglycans, undergo a distinct turnover process during which the catabolism and removal of molecules from the extracellular matrix is in balance with the synthesis and deposition of new molecules.²

Proteoglycans are large macromolecules consisting of multiple chains of glycosaminoglycan disaccharides and oligosaccharides attached to a central protein core that provide a framework for collagen and also bind water and cations, forming a viscous, elastic layer that lubricates and protects the cartilage tissue. The presence of these negatively charged aggregates imparts to the matrix of articular cartilage its strong affinity for water and is the most significant contributor to the biomechanical properties of cartilage. The glycosaminoglycans most common in human connective tissue include the disaccharides keratan sulfate, dermatan sulfate, heparin sulfate and chondroitin sulfate and the oligosaccharide, hyaluronan. They consist of amino sugars, which are repeating disaccharide units composed of a hexuronic acid ( D -glucuronic acid, iduronic acid, or L -galactose) and a hexosamine ( D -glucosamine or D -galactosamine). ^3,4

The main disaccharide units of cartilage glycosaminoglycans are formed by the (1→3) linkage of D -glucuronic acid to N -acetylglucosamine; disaccharide units are linked by β(1→4) galactosamine links. The D -galactosamine residues are sulfated either in position 4 (as in chondroitin-4-sulfate) or 6 (as in chondroitin-6-sulfate). The sulfate groups, together with the carboxyl groups of D -glucuronic acid, are ionized at tissue pH, conferring to the chain a strong global electronegative charge. ^5-10 Inadequate sulfate availability resulting in the production of undersulfated proteoglycans will reduce their electronegative charge and water carrying capacity. ^11,12

Glucosamine (2-amino-2-deoxyalpha- D -glucose) is an aminomonosaccharide that serves as a substrate for the biosynthesis of chondroitin sulfate, hyaluronan, and other macromolecules located in the extracellular cartilage matrix. The conversion of L -glutamine and D -fructose-6-P to L -glutamate and D -glucosamine by L -glutamine- D -fructose-6-P amidotransferase (E.C. 2.6.1.16) is the rate-limiting step in proteoglycan synthesis. ^13-15 This reaction may be bypassed if D -glucosamine is available within the cell cytoplasm. ^16,17 Whatever its source, D -glucosamine is phosphorylated and the resulting D -glucosamine-6-P is acetylated to N -acetyl- D -glucosamine, the common precursor for the biosynthesis of keratan sulfate, dermatan sulfate, chondroitin sulfate and hyaluronan. ^16,17

Chondroitin sulfate is a glycosaminoglycan that is polymerized into long, unbranched polysaccharide chains in which some of the constituent chondroitin moieties (composed of D -glucuronic acid and N -acetyl- D -glucosamine) are sulfated. ¹⁸ Close control of chondroitin sulfate synthesis determines chain length, disaccharide composition and degree of sulfation, which vary with anatomic location, stage of development and age and are heterogeneous. ^19-24 For example, the sulfation pattern of chondroitin disaccharides in normal human articular cartilage varies. The deeper layers of immature cartilage contain 4 times more sulfated residues than the upper regions of the immature tissue contain (as a result of polysulfation of some chondroitin residues in the extracellular matrix of the deeper regions). ^19-21 All regions of the extracellular matrix of immature articular cartilage contain a smaller ratio of chondroitin-6-sulfate to chondroitin-4-sulfate than is typical of the extracellular matrix of articular cartilage in adults. ^19-21

Chondroitin sulfate polymers are secreted into the extracellular matrix covalently bound to proteins, forming protein-polysaccharide complexes called proteoglycans. In a proteoglycan, about 100 chondroitin sulfate chains, each containing 50 to 60 disaccharide units of chondroitin sulfate, are covalently attached to a polypeptide backbone composed of over 2,000 amino acids (the serine-rich core protein with a molecular weight of 250,000 to 300,000 daltons). This covalent O -linkage occurs between a terminal D- xylose or D- galactose residue that had been added to the polysaccharide chain and a serine or threonine residue on the core protein, with one chondroitin sulfate chain per 20 or so amino acid residues. The total molecular weight of an individual proteoglycan monomer is 1,500,000 to 2,500,000 daltons. ⁵

One end of the core protein of a proteoglycan is non-covalently linked to a long polysaccharide filament of hyaluronan through a link protein; the connection is achieved by a globular region of the link protein that surrounds the terminal portion of the core protein and a stretch of 5 disaccharide units along the length of the hyaluronan chain. ^25,26 There are two structurally related N-terminal globular domains, G1 and G2, of which only G1 (and not G2) is involved in the aggregation of proteoglycans with hyaluronan. The interglobular domain joining G1 and G2 contains proteinase-sensitive sequences which appear to be the key sites for cleavage during aggrecan turnover. ⁵ Approximately 100 core proteins are bound to an individual hyaluronan chain, at regular intervals of 300 A, forming a unit of aggrecan, the large molecular mass proteoglycan-hyaluronan aggregate predominant within the extracellular matrix of articular cartilage.
The hydrodynamic properties of this aggregate determine the load-bearing capacity of articular tissue. As the electronegative charges of aggrecan draw water into the tissue, a large osmotic swelling pressure is created that swells and expands the extracellular matrix. This pressure produces tension within the interlacing collagen network of the matrix; balance is achieved when tension in the collagen network prevents further entry of water. Articular cartilage tissue swollen with water expresses substantial compressive resilience and offers considerable resistance to fluid flow and redistribution of water. Fully hydrated articular cartilage tissue behaves as a stiff elastic polymer when exposed to sudden impact loading, with pressure-induced displacement of water from the matrix with little or no effect on matrix macromolecules (although sustained loads will produce slow inelastic deformation). Removal of loading allows re-entry of water and a return to the pre-loading high-tension equilibrium condition. ^5,18,27-29


Age and the Composition of Articular Cartilage

In rabbits, fetal articular cartilage is softer than is adult articular cartilage because fetal articular cartilage contains a greater proportion of polysulfated chondroitin sulfates and therefore its water binding capacity is greater. ³⁰ In rats, as age increases from birth to mature adulthood, the extent to which nonosteoarthritic articular cartilage extracellular matrix chondroitins are sulfated decreases significantly. ³¹ In dogs, increasing age is accompanied by significantly decreased chondroitin sulfate and proteoglycan content of articular cartilage and reduced aggregability of the remaining proteoglycans. ³² Similarly, calf articular cartilage proteoglycans are larger on average than are proteoglycans in nonosteoarthritic adult bovine articular cartilage (and contain larger chondroitin sulfate polymers). ³³ In addition to decreasing average size of matrix proteoglycans and chondroitin polymers, the ratio of chondroitin 6-sulfate to chondroitin 4-sulfate in the extracellular matrix of articular cartilage increases with increasing age. ³⁴

In humans, increasing age is accompanied by a decreasing proportion of chondroitin sulfates in the extracellular matrix of nonosteoarthritic articular cartilage ³⁵ and increases in the ratio of chondroitin 6-sulfate to chondroitin 4-sulfate ^36,37 and in the free glucosamine content of the tissue. 38 Furthermore, the average chondroitin sulfate content of individual articular cartilage proteoglycans decreases, impairing the ability of proteoglycans to aggregate spontaneously with hyaluronan. ³⁹ In addition, the ability of proteoglycans to aggregate spontaneously with hyaluronan is decreased as a result of an increased incidence of defect in the core protein of newly-synthesized proteoglycans. ⁴⁰ Consequently, the aggrecan content of the extracellular matrix of articular cartilage in adults is significantly lower than that in children. ⁴⁰

In “normal but aged” human chondrocytes (mean age of donor: 68.8 +/- 4.2 years), basal (unstimulated) synthesis of matrix-degrading stromelysin-1 and collagenase is significantly greater than in chondrocytes harvested from joints of “normal young adults” (mean age of donor: 28.6 +/- 7.1 years). Therefore, “aging” may sensitize chondrocytes to the effects of accelerators of extracellular matrix degradation and may increase the requirement of chondrocytes for exogenous substrate to support the synthesis of new and replacement matrix macromolecules. ⁴¹


Precipitating Events Producing Cartilage Degeneration and Mechanical Failure

Osteoarthritis is a multifactorial, polygenic disorder involving mechanical, biochemical, environmental, systemic and genetic factors that contribute to imbalance between synthesis and degradation of cartilage matrix. ^42,43 Chronic imbalance in matrix macromolecule turnover producing net loss of articular tissue is a required precursor to the development of osteoarthritis and joint pain.

There are numerous potential etiologic triggers that can initiate the progression of events culminating in tissue failure. For example, quadriceps muscle weakness significantly increases the risk for osteoarthritis in humans ⁴⁴ and laxity in a joint may precede failure of the cartilage matrix. ⁴⁵ Interstitial fluid pressurization during loading contributes more than 90% of load support, shielding the collagen-proteoglycan matrix from excessive stresses and reducing friction at the articular surfaces. ⁴⁶ A chronic imbalance of shock-absorbing and weight–bearing muscles affecting joint alignment ^47,48 or overloading from excessive body weight ⁴⁹ induces a mild yet chronic metabolic imbalance in the affected articular cartilage.

Whenever mechanical stress exceeds the tissue’s load-bearing capacity, chondrocyte and synoviocyte secretion of the cytokines interleukin-1 b (IL-1 b ), interleukin-6 (IL-6) and tumor necrosis factor- a (TNF- a ) and nitric oxide (NO) is stimulated. These cytokines auto-stimulate chondrocyte and synoviocyte secretion of matrix metalloproteinases (collagenase, gelatinase, aggrecanase, elastase, and fibronectin-degrading stromelysin-1) and inhibit chondrocyte synthesis of cartilage-specific proteoglycans and type II collagen. The resulting imbalance between synthesis and degradation of extracellular matrix components results in a net decrease in matrix content of aggrecan, type II collagen and other matrix macromolecules. ^42,43,50

IL-1 b , IL-6, TNF- a and nitric oxide also stimulate the clonal expansion of chondrocytes whose daughter cells may express a “fetal” differentiation pattern during early metabolic imbalance in articular cartilage ⁵¹ and produce inferior repair matrix prone to fibrillation and mechanical failure. ^42,43 Spontaneous repair matrix produced in early asymptomatic subclinical osteoarthritic change exhibits a heterogeneous composition more closely resembling that of fibrous cartilage, ⁵² with inferior biomechanical competence ^53,54 resulting in functional incompetence and perishability. ⁵⁵ In addition, the abnormal newly-synthesized matrix may be fibronectin-deficient or may undergo accelerated hydrolysis of fibronectin by stromelysin-1, in either case disturbing chondrocyte anchorage to the extracellular matrix (“anchorage dependence”) and inducing apoptosis and hypocellularity (chondrocyte survival requires attachment to substrate). ^42,43

In early asymptomatic subclinical osteoarthritic change in humans, reactive proliferation of extracellular articular cartilage matrix results in the production of abnormally large and more extensively sulfated chondroitin sulfate polymers and significantly decreased total glycosaminoglycan content (similar to the matrix of nonosteoarthritic human articular cartilage after partial enzymatic hydrolysis 56 ) and significantly decreased proportion of proteoglycans of nonosteoarthritic molecular sizes. ^57-60 Overall, there is a significantly increased proportion of nonaggregated proteoglycans, significantly decreased average size of proteoglycan aggregates (aggrecan) and incorporation of significantly smaller-than-normal-for-age chondroitin sulfate chains into newly-synthesized proteoglycans, significantly decreased total chondroitin sulfate content (and therefore decreased water binding capacity), and a significantly lower ratio of chondroitin 6-sulfate to chondroitin 4-sulfate. ^21,61-63 Both the abnormally small proteoglycans and the abnormally large proteoglycans are unable to aggregate with hyaluronan to form aggrecan. 64 In addition, osteoarthritic human articular cartilage exhibits increased synthesis of more readily hydrolyzable (easily degradable) collagens. ^65,66

In cell culture, human articular chondrocytes harvested from osteoarthritic joint cartilage produced proteoglycans that differed from those produced by human articular chondrocytes harvested from nonosteoarthritic joint cartilage. ⁶⁷ These proteoglycans resembled “fetal-type” proteoglycans with increased chondroitin 4-sulfate content and an increased percentage of smaller proteoglycans than is typical of the proteoglycans produced by chondrocytes harvested by nonosteoarthritic human articular cartilage. ⁶⁸ The synthesis of temporally inappropriate proteoglycans is accompanied by a significantly accelerated rate of degradation of older, more typical-for-age proteoglycans. ⁶⁹

In a rat model of the initiation of osteoarthritic change, increased mechanical stress on articular cartilage increases the ratio of chondroitin 6-sulfate to chondroitin 4-sulfate in the extracellular matrix. ⁷⁰ Mechanical compression of articular cartilage stimulates intrachondrocytic cyclo-oxygenase activity, resulting in increased production of PGE 2 , an inducer of inducible NO synthase-2 (iNOS) activity; consequently, intrachondrocytic NO production is increased in proportion to the magnitude of compression and increasing local compression increases the recruitment of compression-responsive NO-producing articular chondrocytes. ⁷¹ NO stimulates chondrocytic synthesis of matrix metalloproteinases, ⁷² nascent (inactive) IL-1 b , ^73-75 and interleukin-1-converting enzyme (ICE). ⁷⁶ ICE activates nascent inactive IL-1 b . ⁷⁵ Activated IL-1 b inhibits chondrocytic synthesis of proteoglycans ^73,74 and collagen ^73,74 and stimulates chondrocytic synthesis of stromelysin-1, ⁴¹ collagenase ⁴¹ and a presumptive aggrecanase enzyme that cleaves aggrecan. ⁷⁷ As osteoarthritic change progresses, IL-1 b also stimulates increased NO production; ^78-81 NO further stimulates chondrocytic synthesis of matrix metalloproteinases ⁷² and accelerates the progression of osteoarthritis through the establishment of a cooperative positive feedback cycle. ^82,83 In addition, chondrocytes harvested from osteoarthritic human articular cartilage synthesize growth-related oncogene- a (GRO- a ) in response to IL-1 b ; GRO- a stimulates degradation of fibronectin by stromelysin-1, producing anoikis (cell death resulting from loss of normal cell-substratum contact). ⁸⁴

Chondrocytes harvested from osteoarthritic human joints exhibit a reduced anabolic response to insulin-like growth factor-1 (IGF-1) (“IGF resistance” ^42,85 ) and may have reduced ability to transport glucose from the extracellular fluid into the cell for glycosaminoglycan synthesis. ⁸⁶ Therefore, osteoarthritic chondrocytes may have an increased requirement for glucosamine of extracellular origin. ^42,87-89 In addition, IGF-1 stimulates net synthesis of proteoglycans able to form aggrecan by nonosteoarthritic adult bovine articular chondrocytes in cell culture. ⁹⁰ “IGF resistance” may contribute to the etiology of osteoarthritis by down-regulating the production of replacement aggrecan.

Oxidative stress also may impair the synthesis of matrix macromolecules by articular chondrocytes. Inhibition of chondrocyte γ-glutamyl-cysteine synthetase results in reduced intrachondrocytic glutathione concentration and decreased incorporation of sulfate into newly-synthesized proteoglycans and of proline into newly-synthesized collagen. ⁹¹


Chronic Degeneration of the Extracellular Matrix of Articular Cartilage is a Required Precursor to Osteoarthritis

Changes in the macromolecular composition of the extracellular matrix of articular cartilage are characteristic of clinically apparent osteoarthritis. The ratio of chondroitin 6-sulfate to chondroitin 4-sulfate in the extracellular matrix of the articular cartilage of osteoarthritic mice is significantly greater than the ratio in the extracellular matrix of articular cartilage in age-matched nonosteoarthritic mice. ⁹² Osteoarthritic rat articular cartilage, compared to nonosteoarthritic articular cartilage, exhibits significantly decreased total proteoglycan, chondroitin 4-sulfate and chondoitin 6-sulfate contents and significantly increased stromelysin-1 (fibronectin-degrading) activity. ⁹³ In addition, the percentage of apoptotic chondrocytes in the tissue is significantly increased. ⁹³ Proteoglycans in osteoarthritic adult bovine articular cartilage are larger than normal adult bovine articular cartilage proteoglycans (with larger chondroitin sulfate polymers) and closely resemble proteoglycans found in the articular cartilage matrix of calves. ³³Osteoarthritic equine articular cartilage contains a significantly increased proportion of unsulfated disaccharides and a significantly decreased proportion of chondroitin 6-sulfate. ⁹⁴ The articular cartilage of Cynomolgus macaque monkeys with arthritis exhibits increased production of abnormal chondroitin sulfate-containing polymers. ⁹⁵

In degenerative joint disease in dogs, affected articular cartilage contains significantly increased amounts of newly-synthesized large chondroitin sulfate-rich and glucosamine- and galactosamine-poor proteoglycans typical of those produced by immature canine articular cartilage. ^61,96,97 As cartilage degeneration progresses, affected canine articular cartilage exhibits significantly increased production of abnormal chondroitin sulfate-containing polymers, significantly increased water content, significantly increased proteoglycan content, significantly increased percentage of smaller proteoglycans and significantly decreased percentage of chondroitin sulfate in proteoglycans. ^57,98,99 Some newly synthesized proteoglycans are abnormally large (containing abnormally long chondroitin sulfate chains) and a second population of proteoglycans are abnormally small; both have lost the ability to aggregate spontaneously with hyaluronan, compromising the hydrodynamic properties of the tissue. ¹⁰⁰

Pathologic changes in cartilage matrix composition and organization alter the affinity of the matrix for water and produce excessive cartilage deformation under loading. ^101,102 When chronic, excessive tissue deformation induces adaptive structural and compositional changes that confer increased stiffness in the tissue, ⁴⁵ increasing its vulnerability to the compressive, tensile and shear forces that occur during normal joint function. ¹⁸ Grossly apparent cartilage erosion does not appear until the tissue has lost considerable stiffness and is undergoing progressive mechanical failure. ⁴⁵

As a result of the changes occurring in articular cartilage, abnormally transmitted mechanical stress produces microfractures within the tissue matrix that in turn increase the stresses on surrounding tissue and induce increased chondrocyte secretion of metalloproteinases. ¹⁰³ The subsequent enzymatic tissue degradation potentiates local tissue stress and initiates a positive feedback loop. Increased loading on subchondral bone stimulates the attempt to reduce mechanical stress by increasing joint surface area through the production of bone spurs (osteophytes) at the joint margins (which confer the hard bony enlargement that is characteristic of chronic osteoarthritis). ¹⁰³


The Culmination of Matrix Degeneration in Osteoarthritis

In the US, the incidence of at least one joint with osteoarthritis among those aged 15 to 40 years is about 5%; this increases to over 60% among those over 65 years old. ¹⁰⁴ Overall, the prevalence of at least mildly symptomatic ¹⁰⁵ osteoarthritis in at least one joint is about 30%. Symptomatic osteoarthritis of the knee occurs in about 6% of US adults aged 30 years and older, 106 although radiographic changes of the femorotibial compartment occur in 5% to 15% of people aged 35 to 74 years. ¹⁰⁷

Clinical osteoarthritis (also known as degenerative joint disease) is characterized by focal loss of cartilage and hypertrophic bone spurs. ¹⁰³ Although the term osteoarthritis refers to the overgrowth of bone at the margins and subchondral areas of the joint, and despite the eventual bony involvement in later stages of the disease, osteoarthritis is marked by net loss of cartilage tissue. Initial loss of articular cartilage tissue is mild but may progress to full thickness erosions and eventual bone-to-bone contact (loss of all joint space). Narrowing of the joint space may reflect other degenerative changes in addition to articular cartilage erosion; ¹⁰⁸ as cartilage degeneration progresses, subchondral bone density and volume increase (consistent with increased transmission of load bearing into the subchondral bone). ¹⁰⁹

The primary complaint in osteoarthritis is pain, particularly upon use of the affected joint. ¹⁰³ Pain can be accompanied by varying degrees of joint stiffness, limitation of movement, tenderness and swelling at the joint margins and loss of function. Osteoarthritis often is asymmetric. There are no systemic symptoms outside the affected joint. ¹⁰³

Possible causes of pain in human osteoarthritis include osteophyte growth with stretching of the periosteum, increased intraosseous pressure, microfractures, ligament damage, capsular tension, meniscal injury and synovitis. ¹¹⁰ Radiologically measured decrease in joint space is significantly correlated with increase in pain severity, although the clinical utility of pain assessment as an estimator of joint deterioration is under debate. ¹¹¹


Bioavailability of Supplemental Glucosamine and Chondroitin Sulfates

D -Glucosamine: There are 3 forms of commercially-available D -glucosamine: D -glucosamine (MW: 179), D -glucosamine-HCl (MW: 270) and D -glucosamine sulfate (a derivative of the naturally occurring cartilage extracellular matrix constituent, aminomonosaccharide D -glucosamine; ¹¹² MW: 456). Because of the differences in molecular size, 1500 mg of D -glucosamine-HCl provides as much D -glucosamine as is provided by 2600 mg of D -glucosamine sulfate or 1040 mg of D -glucosamine. A daily intake of 1500 mg of D -glucosamine sulfate is equivalent to a daily intake of between 15 and 30 mg/kg body weight.

In studies in rats, 90% to 95% of ingested D -glucosamine sulfate was absorbed intact into the blood and about 30% of newly absorbed D -glucosamine sulfate was incorporated into newly synthesized proteoglycans in articular cartilage tissues. ^113,114 In studies in humans, consumption of 314 mg of crystalline D -glucosamine sulfate was followed by the absorption of about 280 mg (about 90%) intact into the bloodstream; about 50% of this amount (about 140 mg) survived hepatic first-pass extraction intact. ¹¹⁵ When the consumption of 1884 mg occurred as one bolus or in three divided intakes of 626 mg every 4 hours, there was no difference in total D -glucosamine sulfate bioavailability to systemic tissues (about 40% to 50% of the amount ingested). Other investigators have reported that over 90% of ingested D -glucosamine sulfate was absorbed intact into the human enterohepatic circulation. ^116,117 One investigator reported that about 75% of ingested D -glucosamine sulfate was bioavailable to body tissues following hepatic first-pass extraction. ¹¹⁷

In healthy subjects, ingestion of D -glucosamine sulfate was followed by increased serum sulfate concentration. In contrast, ingestion of sodium sulfate did not effect serum sulfate concentration, suggesting that dietary supplementation with D -glucosamine sulfate might provide D -glucosamine, free sulfate and D -glucosamine sulfate for proteoglycan synthesis. ¹¹⁸

Chondroitin sulfates : In dogs, rats, mice and rabbits, about 0% to 15% of ingested chondroitin sulfates was absorbed intact. ^42,119-124 In these species, absorption favors chondroitin sulfate polymers with molecular weights <14,000 daltons. ¹²⁰ In all species studied, some inorganic SO ^{4 -2} also was absorbed following cleavage of SO ^{4 -2} from the chondroitin sulfate polymers by sulfatases. ^42,119-124

In humans, between 0% and 15% of an oral bolus of chondroitin sulfates is absorbed intact into the blood. ^125-128 In addition, another 10% to 20% is absorbed following hydrolysis to smaller polymers (<5000 daltons) prior to absorption. ^128,129 However, the biological activity of these smaller polymers has been questioned. ¹⁷ The absorption of chondroitin sulfates probably is not nil; the consumption of either 800 mg or 3000 mg of mixed chondroitin sulfates significantly increased plasma chondroitin sulfate concentration 3 hours after ingestion ^130,131 and the consumption of 800 mg daily for 5 days increased plasma chondroitin sulfate concentration from undetectable levels to a mean of 1.80 mcg/mL, suggesting that the systemic bioavailability of intact chondroitin sulfates in humans is about 12% of the amount ingested. ¹³¹


Biochemical and Physiologic Roles of D -Glucosamine in the Preservation of Articular Cartilage

In cultures of chondrocytes harvested from nonosteoarthritic rat articular cartilage, IL-1β inhibits the expression of UDP-glucoronosyltransferase I mRNA, resulting in decreased synthesis of proteoglycans and their precursors. ^132,133 Conversely, IL-1β stimulates intrachondrocytic production of the catabolism-inducing factors, NO and PGE 2 , resulting in increased expression of mRNA coding for the extracellular fibronectin degrading metalloproteinase enzyme, stromelysin-1. ¹³² The addition of D -glucosamine to the culture medium prevented IL-1β-induced inhibition of the expression of UDP-glucuronosyltransferase I mRNA ^132,133 and of proteoglycan synthesis, ^132,133 as well as IL-1β-induced activation of pro-apoptotic nuclear factor K B (NF- K B). 133 The addition of D -glucosamine-HCl to the culture medium of nonosteoarthritic equine articular cartilage explants in organ culture prevented IL-1β-induced increases in the activities of stromelysin-1, collagenase and gelatinase and bacterial lipopolysaccharide (LPS)- and IL-1β-induced increases in the production of NO and PGE 2 and the degradation of extracellular matrix proteoglycans. ^134-137 Similarly, crystalline D -glucosamine sulfate added to the culture media of chondrocytes harvested from osteoarthritic human articular cartilage inhibited the inherent ^138,139 and IL-1β-induced ^132,139 catabolic activity of metalloproteases secreted by the chondrocytes and stimulated the synthesis of physiologically-relevant proteoglycans with chemical characteristics of proteoglycans synthesized by chondrocytes harvested from nonosteoarthritic human articular cartilage. ^138,140 By unknown but presumably similar mechanisms, dietary supplementation with D -glucosamine sulfate (50 mg/kg body weight daily) conferred to rats resistance to kaolin-and adjuvant-induced tibio-tarsal arthritis. ¹⁴¹

Both D -glucosamine-HCl and D -glucosamine sulfate added to the culture medium of nonosteoarthritic rat femoral articular cartilage explants in organ culture significantly increased the rates of collagen and proteoglycan synthesis and partially prevented nonsteroidal anti-inflammatory drug- (NSAID)-induced inhibition of proteoglycan synthesis.
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