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Glucosamine 和Chondroitin 對治療關節炎的探討

要了解關節疾病和治療，必須先了解關節的構造和功用，在得了關節炎後關節軟骨的疾病變化和修復更是不能不知，仿間很多誇大不實的藥品廣告很多，我以一個科學研究者的身份，努力把相關資訊整理出來，提供有需要的人做參考，以期作出微薄的貢獻。
關節液

關節液是一種粘綢、透明、稻草色的液體。關節液是從關節膜微血管內的血漿經由被動超微濾法穿過血管壁而來的透析液(Sander N 1962 ; Hohn RB 1975)。正常的關節液含有少量淋巴球、單核球、巨噬細胞、嗜中性球及少量的嗜酸性球。關節液的主要功能是供應關節軟骨的營養以及潤滑，並可作為關節軟骨的緩衝物。

關節軟骨 

關節軟骨提供一個潤滑、低摩擦力的表面，它可以抵擋以及分散各種活動姿勢和體重所造成的壓力。關節軟骨是一種玻璃質(hyaline)軟骨，位於骨頭末端，它並沒有鈣化。由於缺乏血管、淋巴管或神經的分佈，因此軟骨細胞是藉由關節液供應所需的營養及氣體的交換(Poole CA, 1993)。關節軟骨的外層沒有鈣化，而內層的軟骨經歷了軟骨內生成骨化作用(endochondral ossification)變成骨垢(此字應為骨字旁，但電腦無此字)(epiphysis)。關節軟骨被有系統的分為四個主要部位。最表層為扁平軟骨細胞與含有一層細薄且排列緊湊的膠原纖維所組成，這層與關節表面並行且排為一列而緊貼著關節表面，含少量的聚合素(aggrecan)。中間層含有很多圓形軟骨細胞並且多醣蛋白 (proteoglycan)的含量增加。深層則是由排列成串狀或圓柱狀的低密度軟骨細胞組成，這部分有多量的多醣蛋白和厚的膠原纖維(Baykiss MT et al, 1983) 。最後一層則是鈣化的軟骨，它的功能是作為非鈣化組織與軟骨下的骨頭之間的緩衝區。軟骨下的骨頭與最深層之間的連接處被稱之為“浪潮標記”(tide mark)。


軟骨結構與功能

軟骨是固體能支持重量的結締組織其強度不如骨頭。從組織學與型態學的特徵可以將軟骨分為三種基本型態，即玻質軟骨(hyaline)、彈性軟骨(elastic)以及纖維軟骨(fibrous)三種(Von der Mark K et al, 1986)。玻質軟骨是最常見的型態，例如關節軟骨、脊椎骨、氣管、支氣管皆屬之，玻質軟骨的軟骨細胞合成第二型膠原蛋白和大的多醣蛋白 (Morrison EH et al, 1996)。彈性軟骨與玻質軟骨結構一樣，有強力的彈性與變形能力(deformity)，它含有大量的彈性纖維在基質(matrix)內(Poole AR, 1993)。會厭軟骨、咽喉、耳皆屬於彈性軟骨。第三種為纖維性軟骨，如半月板則屬纖維性軟骨，它是由密集的結締組織和一種呈現直線狀分布的類軟骨細胞(chondrocyte-like)組成，它合成第一型膠原蛋白(Benjamin MJ et al, 1990)。


關節軟骨的修復與改造(remodeling)

軟骨可因為關節的固定、感染、骨關節炎、風濕性關節炎、創傷、摩擦剝落 (frictional abrasion)以及不適當的醫療而造成傷害。在成熟動物的受傷害軟骨，其癒合能力與病灶的深度有絕對的關係(Mankin HJ et al , 1982)。只有當軟骨下的終板(end-plate)被穿入，才有可能成功的修復(De Palma, AF 1966)。玻質軟骨的軟骨細胞幫助癒合的能力(Campbell CJ et al, 1969 ;Meachim G, 1971)和血管系統是扮演發炎與修復過程的主要因素(Mankin HJ et al, 1982; Frost GE et al, 1979)。關節軟骨的傷害可分為兩種型態。

表淺的病灶

將狗的股骨關節軟骨實施人為的外科傷害、關節固定、強力運動，或是任意的使用後腳，並不會使關節軟骨表淺性病灶的癒合受到影響(Frost GE, 1979)。關節軟骨的鈣化軟骨層以上的裂傷，其癒後並不好(Chung HS et al, 1978 ; Wigren A et al, 1978 ; Salter R et al, 1980)。如果骨軟骨細胞是存活的且軟骨網狀物(meshwork)是沒有被傷害的、喪失的基質也沒有超過細胞所能修復的，而只是急性或短暫的喪失軟骨細胞外的基質之非膠原性大分子，則修復是可以成功完成的 (Carterson B, 1990)。在表淺性軟骨病灶發生後，軟骨細胞接近傷口處變成壞死，但是在大約24小時後，這些細胞呈現出有絲分裂的活動增加產生合成多量的聚葡萄糖胺(glycosaminoglycan)和蛋白質 (Mankin HJ et al, 1982 ; Frost GE et al, 1979)。然而，接下來的這些最初的代謝反應對於癒合則沒有更進一步的幫助(Fuller JA et al, 1975 ; Ghadially FN et al, 1977)。

深層的病灶

軟骨的修復過程依照傷害的深淺而有不同的變化，如較深層的傷害且傷害到軟骨下骨頭則會牽連到血管與骨髓細胞而影響到傷口的反應。病灶如果只是發生在軟骨是沒有辦法癒合(Meachim G et al, 1963 ; Mankin HJ et al , 1967, 1974a, 1974b, 1982 ; Fuller JA et al, 1972 ; Ghadially FN et al, 1977 ; Mitchell N et al, 1987 ; Buckwalter et al, 1989, 1990a, 1990b)。在實驗中嚐試性的作一個深入到軟骨下的骨頭傷害，則其軟骨傷口滲出血液而被血液纖維凝塊所覆蓋 (Campbell CJ, 1969)。這些凝塊最後變成血管化並且改變形狀成類似纖維軟骨的物質(Frost GE 1979, Wigren A et al, 1978 ; Cheung HS et al, 1976 ; Mitchell N et al, 1976)，它們改變形狀成類玻質軟骨或很像疤痕密度的膠原組織(Mankin HJ et al, 1982 ; Mitchell N et al, 1976)。這些物質在傷口邊緣和玻質軟骨融合(Frost GE, 1979)。在這傷口旁的軟骨經歷了與表淺病灶相同的變化。在某些情況之下軟骨的修復是不需要血腫與肉芽的形成。 這種修復方法的特徵牽連到軟骨下的骨頭部分骨折修復反應(Stockwell RA et al, 1979)。刺激軟骨下骨頭的骨軟骨細胞的軟骨形成因素是從對側的關節表面的壓力、減少氧氣的張力、與運動(Stockwell RA et al,1979)。Salter和他的實驗小組發現在患有股骨膝蓋的軟骨骨折或是在軟骨下鑽洞到軟骨下軟骨的兔子，其藉由被動運動(passive motion)施行於兔子腳的遠端可使骨軟骨細胞形成而使軟骨癒合。當被動運動持續的在進行，肉芽組織就無法形成，而是直接形成軟骨。手術後的一週內，被動運動的作用是最明顯的(Salter R et al, 1980)。關節軟骨表面的病灶大小和病兆的位置也與修復有關，太大的骨軟骨傷口無法做一個有效的修復，如果病灶部位是位於重量壓力區將使癒合時間延後，然而病灶是接近關節軟骨周圍則癒合會更快速(Thompson RC, 1975)。 


影響軟骨癒合的因素

正確的對整性和壓力可使關節內的軟骨以玻質軟骨方式癒合(Mitchell N et al, 197)。電的刺激可以促進軟骨癒合(Baker B et al, 1974 ; Brighton CT et al, 1984 ; Aaron RK et al, 1987)。骨膜與軟骨移植可以促進關節軟骨的修復(Skoog T et al, 1972 ; Tonna EA et al, 1972 ; Ohlsen L, 1978 ; Kleiner JB et al, 1986 ; Zarnett R et al, 1987 ; Kwan MK et al, 1987 ; Delaney JP et al, 1989)。軟骨細胞或間葉細胞的植入也可促進軟骨的修復(Kawabe N et al, 1989 ; Robinson D et al, 1989)。植入天然的或是合成的基質(matrices)可以促進關節的修復。形成血管化組織的纖維凝塊可藉由刺激血小板去釋放生長因子因此導致傷口部位的細胞移行和增生來促進癒合(Nemeth GG et al, 1988 ; Arnoczky A et al, 1988)。1977 Farkas 等人與1982年 Mankin 曾經將生理食鹽水或酵素灌入到受傷的組織使前列腺素破壞，因此幫助纖維凝塊的形成。有些研究使用碳纖維植入，與膠原或纖維凝膠注入到受傷的軟骨來促進癒合(Hart JAL, 1987, Grands DA et al 1988. Wakitani S et al, 1989)。生長因子影響許多軟骨細胞和間葉細胞的功能，包括細胞的移行、分裂、生長、增生和細胞外基質形成(Nemeth GG et al, 1988)。關節內給予低劑量的木瓜蛋白酵素(papain)可使軟骨的剝落傷害癒合更有效(Farkas T et al, 1977)。使用骨切開術(osteotomy)改變關節的受力和肌肉的施力方式以減少受傷軟骨的負荷，都可以用來刺激軟骨修復(Weisl H, 1980 ; Radin EL et al, 1982)。


多醣蛋白 (proteoglycans) 

多醣蛋白是一種蛋白質，在軟骨中含有聚合素(aggrecan)，它是多醣蛋白的主要形式，是非常大的分子(重約2x103kDa)，結構與瓶刷類似。它也含有琉璃糖碳基酸(hyaluronic acid)可以和連結蛋白(link proteins)，以非共價(noncovalenty)的方式和核心蛋白與三個球狀的大份子結構(G1, G2, G3) (Heinegard D et al, 1989)和聚葡萄糖胺(GAGs)組成(見圖)，聚葡萄糖胺大約含有30個Keratan sulfate, 100個chondroitin-6-sulfate和chodoitin-4-sulfate 旁鏈於第二和第三的球狀的大份子結構中(Poole AR, 1993)。至少有七種聚葡萄糖胺。就是 hyaluronic acid， chondroitin sulfate， keratan sulfatesⅠandⅡ， heparin， heparin sulfate and dermatan sulfate. 聚葡萄糖胺鏈包含碳基(carboxyl)和硫酸基(sulfate) 的陰性電荷，它可以使聚合素結合大量的水份來創立一個含高水化合物的基質(Poole AR, 1986)，所以軟骨含有高水份而有避震的作用。

Glucosamine和 Chondroitin 效用研究報告

葡萄糖胺(Glucosamine)是聚葡萄胺的先成物質(Menzel EJ. 2000)，軟骨素(chondroitin)也是聚葡萄糖胺的成分，理論上這些物質被吸收後應該形成軟骨的一部份而且部份glucosamine也要變成琉璃糖碳基酸的成分以增加關節液的潤滑，從以下研究文獻上證明，事實是有這樣的作用 (Johnson KA et al,2001，McCarty MF et al 2000 Bali JP et al 2001 Echard BW et al 2001 Das A Jr et al 2000 Mazieres B et al 2001 Noack W et al 1994 Muller-Fassbender H et al 1994 pain released Bucsi L et al 1998 chondroitin Pavelka K, et al 2002 Reginster JY et al 2001 Reichelt A et al 1994 Houpt JB 1999 Bourgeois P et al ,1998 chondroitin Conrozier T 1998 Delafuente JC 2000 Pavelka K Jr et al 1995 Leeb BF et al 2000 Kelly GS.1998 Towheed TE 2001 Ruane R et al 2002 Qiu GX et al 1998 Pujalte JM et al 1980 Lippiello L et al 2000 McAlindon TE et al 2000 Fenton JI et al 2000 Rubin BR et al 2001 Pipitone VR 1991 chondroitin) 但是所有有效的研究文獻裡沒有一個的有效率和對照組比較是超過50%，也就是兩個patients 裡有一個是無效，有效也不是把病治好，只是症狀減輕，並沒有像一些市面上所宣傳的那麼好，在前面軟骨的修復已經談過，軟骨一旦被破壞就很難修復，所以吃下的的glucosamine和 chondroitin無法完全修復軟骨，只能提供保護作用，在破壞大於修復的情況下所吃的藥就無法顯現其效果，另外以下的文獻報告是無效的(Hughes R et al 2002 Rindone JP et al 2000， Pavelka K et al 2000， Rindone JP al 2000) 或不建議使用Leffler CT et al 1999， O'Rourke M O'Rourke M 2001 認為現在還不適合推薦 da Camara CC et al 1998和Brief AA et al 2001 認為研究報告的實驗設計有瑕疵，不能太信任有效的結果，Chard J et al 2001 認為沒有好的證明說它有效，Barclay TS et al 1998 認為須作更多的研究才能確定， Glucosamine雖然副作用很少，但是還是會有胃腸障礙，過敏皮膚癢，有糖尿病者會引起胰島素的耐藥性(Yoshikawa H et al 2002)，另外最近也有研究報告顯示glucosamine會抑制白血球的嗜中性球的功用，降低白血球的吞噬能力(Hua J et al 2002)。

由上的研究報告得知，公說公有理，很難取捨要不要給狗吃glucosamine和chondroitin，較多的研究報告是正面的，我想在沒有經濟因素的考慮下，可以由飼主自己考量和注意副作用的產生，一旦讓她服用感覺不對立即停藥，因為缺乏狗的劑量研究報告，最好一天不要超過1000mg，因為有最新的研究報告顯示使用過量的glucosamine於牛的軟骨細胞培養基裡會造成牛的軟骨細胞的破壞(de Mattei M et al 2002)，glucosamine和chondroitin 在研究報告裡顯示2個月後才能見效果，長期服藥需要定期血檢以免肝腎有問題不知減量或停藥造成傷害，如果服用一段時間未見藥效(症狀減輕)，我想你家的狗狗為無效的那一類，應該停止服用，以免當白老鼠，glucosamine和chondroitin尚未被美國FDA核准，應該小心使用。

運動和物理治療

最好的保健應是不要劇烈的運動和跳躍，也不要讓犬後腳站立走路，同時游泳是最好的無負重運動，在無負重的運動下，可以刺激軟骨細胞和關節囊膜細胞產生潤滑液(含有多量的琉璃糖碳基酸亦即玻尿酸)，以保護關節軟骨不受重力傷害，除了運動，物理治療也很重要(Deyle GD et al 2001)，最好的物理治療是讓狗躺下，把腿像走路的方式來回移動，切忌往關節窩的方向施加壓力，這樣的方式也是一種無重力的運動，每天物理治療20分鐘或一週游泳2-3次是個很好的保健方式而且不必擔心服藥的副作用。


參考文獻 Referance

1. Aaron PK, et al: stimulation of proteoglycan synthesis in articular chondrocyte cultures by a pulsed electromagnetic field. Trans Orthop Res Soc. 1987, 12: 273
2. Arnoczky A, et al: In Injury and Repair of the Musculoskeletal Soft Tissue (S.L. Woo and J.A. Buckwalter, eds). American Academy of Orthopeadic Surgeons, Park Ridge, IL 1988, Chap. 12, p 487-537
3. Baker B, et al: A study of electrochemical enhancement of articular cartilage repair. Clin. Orthop. 1974, 102: 251
4. Bali JP, Cousse H, Neuzil E. Biochemical basis of the pharmacologic action of chondroitin sulfates on the osteoarticular system. Semin Arthritis Rheum 2001 Aug;31(1):58-68
5. Barclay TS, Tsourounis C, McCart GM. Glucosamine. Ann Pharmacother 1998 May;32(5):574-9
6. Bayliss MT, et al: Structure of proteoglycans from different layers of human articular cartilage. Biochemical Journal. 1983, 209: 387-400
7. Benjamin MJ et al: Fibrocartilage. Journal of Anatomy. 1990, 171: 1-15 
8. Buckwalter JA, et al: Articular cartilage repair in osteoarthritis. In Osteoarthritis: Diagnosis and Management (D.S. Howell, H.J. Mankin, R. W. Moskowitz and W.B. Saunders, eds), 2nd edt. (in press), 1990a
9. Bourgeois P, Chales G, Dehais J, Delcambre B, Kuntz JL, Rozenberg S. Efficacy and tolerability of chondroitin sulfate 1200 mg/day vs chondroitin sulfate 3 x 400 mg/day vs placebo. Osteoarthritis Cartilage 1998 May;6 Suppl A:25-30
10. Brief AA, Maurer SG, Di Cesare PE. Use of glucosamine and chondroitin sulfate in the management of osteoarthritis. J Am Acad Orthop Surg 2001 Mar-Apr;9(2):71-8
11. Buckwalter JA, et al: Articular cartilage: composition structure, response to injury and methods of facilitating repair. In Articular Cartilage and Knee Ioint Function: Basic Science and Arthroscopy (J.W. Ewing, ed.), Chap. 2. Raven Press, New York, 1990b
12. Bucsi L, Poor G. Efficacy and tolerability of oral chondroitin sulfate as a symptomatic slow-acting drug for osteoarthritis (SYSADOA) in the treatment of knee osteoarthritis. Osteoarthritis Cartilage 1998 May;6 Suppl A:31-6
13. Conrozier T. [Anti-arthrosis treatments: efficacy and tolerance of chondroitin sulfates (CS 4&6)] Presse Med 1998 Nov 21;27(36):1862-5
14. Delafuente JC. Glucosamine in the treatment of osteoarthritis. Rheum Dis Clin North Am 2000 Feb;26(1):1-11, vii
15. De los Reyes GC, Koda RT, Lien EJ. Glucosamine and chondroitin sulfates in the treatment of osteoarthritis: a survey. Prog Drug Res 2000;55:81-103
16. De Mattei M, Pellati A, Pasello M, de Terlizzi F, Massari L, Gemmati D, Caruso A. High doses of glucosamine-HCl have detrimental effects on bovine articular cartilage explants cultured in vitro. Osteoarthritis Cartilage 2002 Oct;10(10):816
17. Das A Jr, Hammad TA. Efficacy of a combination of FCHG49 glucosamine hydrochloride, TRH122 low molecular weight sodium chondroitin sulfate and manganese ascorbate in the management of knee osteoarthritis. Osteoarthritis Cartilage 2000 Sep;8(5):343-50
18. De Palma, AF et al: Process of repair of articular cartilage demonstated by histology and autoradiography with tritiated thymidine. Clin. Orthop. 1966, 48: 229
19. Delaney JP, et al: Neochondrogenesis in free intra-articular periosteal autografts in an immobilized and paralyzed limb. Clin. Orthop. 1989, 248: 278-282
20. Deyle GD, Henderson NE, Matekel RL, Ryder MG, Garber MB, Allison SC. Effectiveness of manual physical therapy and exercise in osteoarthritis of the knee. A randomized, controlled trial. Ann Intern Med 2000 Feb 1;132(3):173-81
21. Echard BW, Talpur NA, Funk KA, Bagchi D, Preuss HG. Effects of oral glucosamine and chondroitin sulfate alone and in combination on the metabolism of SHR and SD rats. Mol Cell Biochem 2001 Sep;225(1-):85-91
22. Farkas T, et al: Papain induced healing of superficial lacerations in articular cartilage of adult rabbits. Trans. Orthop. Res. Soc. 1977, 2: 204
23. Frost GE, et al: Cartilage healing and regeneration. J South African Vet Associ 1979, 50: 181
24. Fuller JA, et al: Ultrastructural obserbations on surgically produced partial thickness defects in articular cartilage. Clin. Orthop. 1972, 86: 193
25. Ghadially FN: Fine structure of joints. In The Joints and Synovial Fluid, Vol. I. Edited by l. Sokoloff. New York, Academic Press, 1978
26. Grande DA, et al: The use of adhesives in chondrocyte transplantation surgery preliminary studies. Bull. Hosp. Joint Vis. Orthop. Inst. 1988, 48: 140-148
27. Hart JAL: The use of carbon fibre implants for articular cartilage defects. Presented at the 47th Annual Meeting of the Australian Orthopaedic Association, Melbourne, 1987
28. Hohn, RB, et al: Surgical repairs of ligamentous structures of the stifle joint. In Current Techniques in Small Animal Surgery. Edited by M.J. Bojrab. Philadelphia,Lea & Febiger, 1975, p470
29. Hoffer LJ, Kaplan LN, Hamadeh MJ, Grigoriu AC, Baron M. Sulfate could mediate the therapeutic effect of glucosamine sulfate. Metabolism 2001 Jul;50(7):767-70
30. Houpt JB, McMillan R, Wein C, Paget-Dellio SD. Effect of glucosamine hydrochloride in the treatment of pain of osteoarthritis of the knee. J Rheumatol. 1999 Nov;26(11):2294-7 
31. Hughes R, Carr A. A randomized, double-blind, placebo-controlled trial of glucosamine sulphate as an analgesic in osteoarthritis of the knee. Rheumatology (Oxford) 2002 Mar;41(3):279-84
32. Hughes R, Carr A. A randomized, double-blind, placebo-controlled trial of glucosamine sulphate as an analgesic in osteoarthritis of the knee. Rheumatology (Oxford) 2002 Mar;41(3):279-84
33. Johnson KA, Hulse DA, Hart RC, Kochevar D, Chu Q. Effects of an orally administered mixture of chondroitin sulfate, glucosamine hydrochloride and manganese ascorbate on synovial fluid chondroitin sulfate 3B3 and 7D4 epitope in a canine cruciate ligament transection model of osteoarthritis. Osteoarthritis Cartilage 2001 Jan;9(1):14-21
34. Kawabe N, et al: The repair of full thickness articular cartilage defects. Immune responses to reparative tissue by growth plate chondrocytes implants. Trans. Orthop. Res. Soc.1989, 14: 143 
35. Kelly GS. The role of glucosamine sulfate and chondroitin sulfates in the treatment of degenerative joint disease. Altern Med Rev 1998 Feb;3(1):27-39
36. Kleiner JB, et al: The short term evaluation of different treatment modalities upon full thickness articular cartilage defects: a study of rib perichondrial chondrogenesis. Trans Orthop. Res. Soc. 11: 282
37. Kwan MK, et al: Neocartilage generated from rib perichondrium: a long-term multidisciplinary evaluation. Trans. 33rd Orthop. Res. Soc. Meeting, 1987, p12-277
38. Leffler CT, Philippi AF, Leffler SG, Mosure JC, Kim PD. Glucosamine, chondroitin, and manganese ascorbate for degenerative joint disease of the knee or low back: a randomized, double-blind, placebo-controlled pilot study. Med 1999 Feb;164(2):85-91
39. McCarty MF, Russell AL, Seed MP. Sulfated glycosaminoglycans and glucosamine may synergize in promoting synovial hyaluronic acid synthesis. Med Hypotheses 2000 May;54(5):798-802
40. Gramajo RJ, Cutroneo EJ, Fernandez DE, Gibson JL, Caceres Maldonado JC, Romero FL, Houssay RH. A single-blind, placebo-controlled study of glycosaminoglycan-peptide complex ('Rumalon') in patients with osteoarthritis of the hip or knee.
42. Lippiello L, Woodward J, Karpman R, Hammad TA. In vivo chondroprotection and metabolic synergy of glucosamine and chondroitin sulfate. Clin Orthop 2000 Dec;(381):229-40
43. Leeb BF, Schweitzer H, Montag K, Smolen JS. A metaanalysis of chondroitin sulfate in the treatment of osteoarthritis. J Rheumatol 2000 Jan;27(1):205-11
44. Mankin HJ, et al: The acute effects of lacerative injury on DNA and protein synthesis in articular cartilage. In Cartilage Degradation and Repair (A.L. Bassett, ed.), National Acad. Sci. National Research Council, Washington DC, 1967, 186-199. 
45. Mankin HJ: The reaction of articular cartilage to injury and osteoarthritis: Part I. N. Engl. I. Med. 1974a, 291:1285-1292
46. Mankin HJ, et al: The response of articular cartilage to mechanical injury. J. Bone Joint Surg. 1982, 64A: 460-466
47. Mazieres B, Combe B, Phan Van A, Tondut J, Grynfeltt M. Chondroitin sulfate in osteoarthritis of the knee: a prospective, double blind, placebo controlled multicenter clinical study. J Rheumatol 2001 Jan;28(1):173-81
48. McAlindon T. Glucosamine and chondroitin for osteoarthritis? Bull Rheum Dis 2001 Jul;50(7):1-4
49. McAlindon TE, LaValley MP, Gulin JP, Felson DT. Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. JAMA 2000 Mar 15;283(11):1469-75
50 McCarty MF. The neglect of glucosamine as a treatment for osteoarthritis--a personal perspective. Med Hypotheses 1994 May;42(5):323-7
51. McCarty MF. Glucosamine may retard atherogenesis by promoting endothelial production of heparan sulfate proteoglycans. Med Hypotheses 1997 Mar;48(3):245-51
52. Meachim G: The effect of scarification on articular cartilage in the rabbit. J. Bone Joint Surg. 1963, 458:150-161
53. Meachim G et al: Repair of joint surface from subarticular tissue in the rabbit knee. J Anat. 1971, 109: 317 
54. Mitchell N, et al: Effect of patellar shaving in the rabbit. J. Orthop. Res. 1987, 5:388-392
55. Mitchell N, et al: the resurfacing of adult rabbit articular cartilage by multiple perforations through the subchondral bone. J. Bone Joint Surg. 1976, 58A: 230
56. Morrison EH, et al: The development of articular cartilage: I. The spatial and temporal patterns of collagen types. Journal of Anatomy. 1996, 189: 9-22
57. Muller-Fassbender H, Bach GL, Haase W, Rovati LC, Setnikar I. Glucosamine sulfate compared to ibuprofen in osteoarthritis of the knee. Osteoarthritis Cartilage 1994 Mar;2(1):61-9
58. Nemeth GG, et al: Growth factors and their role in wound and fracture healing. In Growth Factors and Other Aspects of Wound Healing: Biological and Clinical Implications (Barbule, Pines, Caldwell and Hunt, eds), 1988, p1-17. Allen R. Liss, New York
59. Noack W, Fischer M, Forster KK, Rovati LC, Setnikar I. Glucosamine sulfate in osteoarthritis of the knee. Osteoarthritis Cartilage 1994 Mar;2(1):51-9
60. Ohlsen L: Cartilage regeneration from perichondrium. Plastic Reconst. Surg. 1978, 62: 507-513
61. O'Rourke M. Determining the efficacy of glucosamine and chondroitin for osteoarthritis. Nurse Pract 2001 Jun;26(6):44-6, 49-52
62. Pavelka K, Gatterova J, Olejarova M, Machacek S, Giacovelli G, Rovati LC. Glucosamine Sulfate Use and Delay of Progression of Knee Osteoarthritis: A 3-Year, Randomized, Placebo-Controlled, Double-blind Study. Arch Intern Med 2002 Oct 14;162(18):2113-23
63. Pavelka K Jr, Sedlackova M, Gatterova J, Becvar R, Pavelka K Sr. Glycosaminoglycan polysulfuric acid (GAGPS) in osteoarthritis of the knee. Osteoarthritis Cartilage 1995 Mar;3(1):15-23
64. Phoon S, Manolios N. Glucosamine. A nutraceutical in osteoarthritis. Aust Fam Physician 2002 Jun;31(6):539-41
65. Poole AR: Proteoglycans in health and disease: structures and functions. Biochemical Journal. 1986, 236: 1-14. 
66. Poole AR, et al: Cartilage in health and disease. In arthritis and Allied Conditions. A Textbook of Rheumatology. D.J. Mccarty, and W.J. Koopman, editors. Lea and Febiger, Philadelphia. 1993, 279-333
67. Poole CA, et al: The structure and function of articular cartilage matrices. In joint cartilage degradation. Basic and Clinical Aspects. JF Woessner, Jr., and DS Howell, edit. Marcel Dekker, INC, New York. 1993, 1-36
68. Pujalte JM, Llavore EP, Ylescupidez FR. Double-blind clinical evaluation of oral glucosamine sulphate in the basic treatment of osteoarthrosis. Curr Med Res Opin 1980;7(2):110-14
69. Qiu GX, Gao SN, Giacovelli G, Rovati L, Setnikar I. Efficacy and safety of glucosamine sulfate versus ibuprofen in patients with knee osteoarthritis. Arzneimittelforschung 1998 May;48(5):469-74
70. Reichelt A, Forster KK, Fischer M, Rovati LC, Setnikar I. Efficacy and safety of intramuscular glucosamine sulfate in osteoarthritis of the knee. A randomised, placebo-controlled, double-blind study. Arzneimittelforschung 1994 Jan;44(1):75-80
71. Rindone JP, Hiller D, Collacott E, Nordhaugen N, Arriola G. Randomized, controlled trial of glucosamine for treating osteoarthritis of the knee. West J Med 2000 Feb;172(2):91-4
72. Robinson D, et al: The influence of the host's age on the fate of implants of embryonal chondrocytes into articular surfaces. Mech. Aging Dev. 1989, 51: 71-80
Rovati LC. Clinical research in osteoarthritis: design and results of short-term and long-term trials with disease-modifying drugs. Int J Tissue React 1992;14(5):243-51
73. Ruane R, Griffiths P. Glucosamine therapy compared to ibuprofen for joint pain.
Br J Community Nurs 2002 Mar;7(3):148-52
74. Russell AL. Glucosamine in osteoarthritis and gastrointestinal disorders: an exemplar of the need for a paradigm shift. Med Hypotheses 1998 Oct;51(4):347-9
75. Salter R, et al: the biological effect of continuous passive motion on the healing of full-thickness defects in articular cartilage. J. Bone Joint Surg. 1980, 62A: 1232
Sanders N: Lameness and allied conditions in the greyhound. Aust. Vet. J. 1962, 38: 239
76. Shankland WE 2nd. The effects of glucosamine and chondroitin sulfate on osteoarthritis of the TMJ: a preliminary report of 50 patients. Cranio 1998 Oct;16(4):230-5
77. Skoog T, et al: Perichondral potential for cartilaginous regeneration. Scand. J. Plast. Reconstruct. Surg. 1972, 6: 123-125 
78. Stockwell RA, et al: The chondrocytes. In Adult Articular Cartilage (2nd Ed.) edited by Freeman MAR, London, Pitman 1979
79. Takeda W, Wessel J. Acupuncture for the treatment of pain of osteoarthritic knees. Arthritis Care Res 1994 Sep;7(3):118-22
80. Textbook of Rheumatology. D.J. Mccarty, and W.J. Koopman, editors. Lea and Febiger, Philadelphia. 1993, 279-333
81. Thompson RC, JR: An experimental study of surface injury to articular cartilage and enzyme responses within the joint. Clin Orthop 1975, 107: 239-248
82. Tonna EA, et al: Chondrogenic cell formation via osteogenic cell progeny transformation. Lab. Invest. 1972, 27: 418-426
83. Towheed TE, Anastassiades TP, Shea B, Houpt J, Welch V, Hochberg MC. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev 2001;(1):CD002946
84. Walker-Bone K, Javid K, Arden N, Cooper C. Glucosamine and chondroitin may help in osteoarthritis. BMJ 2001 Mar 17;322(7287):673
85. Wakitani S, et al: Repair of rabbit articular surfaces with allograft chondrocytes embedded in collagen gel. I. Bone Joint Surg.1989, 718: 74-80
86. Weisl H: Intertrochanteric osteotomy for osteoarthritis. A long-term follow-up. J. Bone Joint Surg. 1980, 628,37-42
87. Wigren A, et al: The healing of cartilage injuries under the influence of joint immobilization and repeated hyaluronic acid injections. An experimental study. Acta Orthop. Scand. 1978, 49: 121
88. Zarnett R, et al: Cellular origin and evolution of neochondrogenesis in major full thickness defects of a joint surface treated by free autogenous periosteal grafts and subjected to continous passive motion in rabbits. Clin. Orthop.1987, 222: 267-274