Osteoarthritis, also known as degenerative joint

Transcription

1 This rticle is protected by copyright. To shre or copy this rticle, plese visit copyright.com. Use ISSN# X. To subscribe, visit imjournl.com ORIGINAL RESEARCH An Osteoinductive Protein Complex Tht Stimultes Regenertion of Bone nd Crtilge for Tretment of Moderte to Severe Osteorthritis Richrd Grin, DC, MS; Arlene Donr, ND; Donld DeFbio, DC; Nncy Ghles, DC; Jmes J. Scffidi, BS Abstrct Context: Osteorthritis, lso known s degenertive joint disese, is one the most common forms of joint disorder in the United Sttes nd ffects over 20 million people. Current tretments for its mngement involve the use of nlgesics such s cetminophen nd nonsteroidl, nti-inflmmtory drugs (NSAIDs). These tretments, however, hve shown limited effectiveness, nd in some cses, hve produced severe side effects, including GI conditions, internl bleeding, nd kidney dmge. Objective: The study intended to demonstrte the clinicl effects of novel protein complex, Cyplexinol, in combintion with glucosmine nd chondroitin, in the regenertive stimultion of bone nd crtilge to reduce pin nd increse joint flexibility in helthy individuls with degenertive joint disese due to osteorthritis. Design: The reserch tem conducted n open-lbeled, rndomized, prospective, multicenter tril. Setting: The offices of the four licensed helth-cre professionls were the four centers in which the tril took plce. Prticipnts: Prticipnts were ptients t the four helth-cre centers 18 women nd 10 men with men ge of 61 yers. Intervention(s): In this tril, the 28 rndomized prticipnts in the intervention group received combintion of Cyplexinol, bone morphogenetic protein (BMP) complex, plus glucosmine nd chondroitin, three times dy. The totl dily dose ws 150 mg of Cyplexinol, 1500 mg of glucosmine sulfte, nd 1200 mg of chondroitin sulfte for period of 4 weeks. Outcome Mesure(s): The reserch tem evluted pin nd joint flexibility using visul nlog scle (VAS). Prticipnts completed the questionnire t bseline nd weekly therefter to llow the reserch tem to ssess the effectiveness of the product. Results: Bsed on the comprison of men vlues reported t bseline, the reserch tem noted significnt reduction t the end of the tril in overll pin (54.7%) s well s frequency of pin (58.8%) in the ffected joints. Similrly, significnt reduction in pin nd stiffness ws reported during recretion/ctivity s prticipnts moved the ffected joints. This reduction in pin trnslted into n increse in the strength of the ffected joints nd n increse in overll ctivity for prticipnts. Conclusions: The results of this tril suggest tht the combintion of Cyplexinol, which contins BMPs nd growth fctors, plus glucosmine nd chondroitin, reduced joint pin nd stiffness effectively in individuls with reduced joint function ssocited with osteorthritis. Richrd Grin, DC, MS, hs privte prctice in Frminghm, Msschusetts. Arlene Donr, ND, hs privte prctice in New York, New York. Donld DeFbio, DC, hs privte prctice in Berkeley Heights, New Jersey. Nncy Ghles, DC, hs privte prctice in Belle Hrbor, New York. Jmes J. Scffidi, BS, is CEO/president of ZyCl Bioceuticls, Inc, in Toms River, New Jersey. Corresponding uthor: Jmes J. Scffidi, BS E-mil ddress: jscffidi@zyclbio.com Osteorthritis, lso known s degenertive joint disese, is one the most common forms of joint disorder in the United Sttes nd ffects over 20 million people. 1-3 It is cused by the progressive brekdown nd eventul loss of crtilge in the joints, ffecting mostly the hnds, feet, spine, hips, nd knees. Avilble therpies for osteorthritis primrily ddress the tretment of the ptients joint pin. 4 Current tretments for the mngement of osteorthritis involve the use of nlgesics such s cetminophen nd nonsteroidl, nti-inflmmtory drugs (NSAIDs). These tretments, however, hve shown limited effectiveness, nd in some cses, hve produced severe side effects, including GI conditions, 16 Integrtive Medicine Vol. 11, No. 5 October 2012 Grin Osteoinductive Protein Complex for Osteorthritis

2 This rticle is protected by copyright. To shre or copy this rticle, plese visit copyright.com. Use ISSN# X. To subscribe, visit imjournl.com internl bleeding, nd kidney dmge. 5-7 In ddition to NSAIDs, the dietry supplements glucosmine nd chondroitin sulfte, lone or in combintion, hve been commonly used in tretment of the symptoms of osteorthritis nd hve been dvocted s sfe, but they hve shown mixed results for the disese s mngement. Both of these nutrients re nturlly found in nd round the cells of crtilge. Glucosmine is n mino sugr tht is produced in the body nd is distributed in crtilge nd other connective tissue. Chondroitin sulfte is complex crbohydrte tht helps crtilge to retin wter. In severl clinicl trils, the effectiveness of glucosmine nd chondroitin sulfte hs been investigted. Among these studies, two mjor, humn clinicl trils hve investigted the role of these two dietry supplements. The Glucosmine/chondroitin Arthritis Intervention Tril (GAIT), 1583-ptient, 6-month tril sponsored by the Ntionl Institutes of Helth, 8 filed to show significnt improvement in the overll ptient popultion for glucosmine, chondroitin, or their combintion. The results of nother tril with 318 prticipnts treted for 6 months the Glucosmine Unum In Die (once--dy) Efficcy (GUIDE) showed smll 5% to 6% improvement over plcebo for glucosmine sulfte in the scores on the totl Western Ontrio nd McMster Universities Osteorthritis (WOMAC) Index. 9 Becuse of the limited effectiveness of these tretments, the serch for lterntive nd complementry tretments for osteorthritis continues. Conventionl therpies hve been designed to minimize the effects of the inflmmtory response, which excerbtes the overll pthology, nd hve hd miniml effects on the syndrome s etiology. In recent yers, investigtors hve ttempted to isolte nd study the effect of proteins tht stimulte regenertion of bone nd crtilge by ctivting mesenchyml stem cells (MSC) nd differentiting them into osteoblsts nd chondrocytes tht in turn promote bone-nd-crtilge formtion de novo Bone Morphogenetic Proteins (BMPs) hve been shown to be the key osteoinductive proteins responsible for ctivting MSC, supported with key growth fctors (TGF-β, IGF, nd bfgf) for cellulr mturtion. These osteoinductive proteins exhibit cpbilities for joint-tissue repir s well s intrinsic nti-inflmmtory properties, both of which re essentil for repiring tissue dmge in rthritic ptients In recent effort to develop more effective supplement for individuls with joint pin, unique complex of osteoinductive proteins, known s Cyplexinol, hs been discovered. The reserch tem combined this protein complex with glucosmine nd chondroitin nd investigted the combintion to determine its effectiveness in reducing pin nd incresing joint flexibility in individuls with degenertive joint disese due to osteorthritic conditions. Methods Prticipnts The four licensed helth-cre professionls, who were members of the reserch tem for the present study nd re four of the uthors of this rticle, provided the four centers for the multicenter tril t their respective offices. To be eligible, ptients must hve been 18 yers of ge or older nd must hve been dignosed with moderte-tosevere osteorthritic condition in the hip or knee by helth-cre professionl. Ptients were excluded from the tril if they were tking glucosmine/chondroitin/msm/ SAMe, omeg-3, or ny herbl product or other supplement for pin or inflmmtion of the joints. They were lso excluded if they were tking ny NSAIDs, COX-2 inhibitors, DMARDs, steroids/corticosteroids, TNF blockers, nrcotics, or ny controlled substnces for pin s prescribed by physicin. Other exclusion criteri included (1) being pregnnt or nursing womn, (2) hving dibetes, (3) being llergic to shellfish, nd (4) hving rheumtoid or nother form of rthritis. The study lso excluded individuls who could not or were unwilling to interrupt the intke of mediction or supplement for joint helth for t lest 1 month prior to beginning the tril. Twenty-eight rndomized ptients 18 women nd 10 men with men ge of 61 yers were enrolled. To mintin nonymity, prticipnts were lphbetized nd then rndomly ssigned number by selecting odd nd even numbers from rndom number tble. Prior to the strt of the tril, prticipnts were required to hve physicl exm nd medicl-history exm by one of the four licensed helth-cre professionls mnging the study s well s to complete n initil visul nlog scle (VAS) questionnire to estblish bseline. 16 In ddition to the physicl nd medicl-history exm, n x-ry of the knee or hip joint ws completed, t the discretion of the helth-cre professionl, to further support the dignosis. Intervention The tril ws conducted s n open-lbeled, rndomized, prospective, multicenter study. The test supplement used in this tril ws combintion of Cyplexinol, which consists of Bone Morphogenetic Proteins (BMPs) tht stimulte the regenertion of bone nd crtilge, plus glucosmine nd chondroitin. BMPs belong to the TGF-bet superfmily, which includes the following growth fctors tht lso re present in the supplement: (1) trnsforming growth fctor bet (TGFβ), (2) insulin-like growth fctor (IGF), (3) bsic fibroblst growth fctor (bfgf), nd (4) vsculr endothelil growth fctor (VGEF). Tretment consisted of orl doses of Cyplexinol plus glucosmine nd chondroitin in combined tblet, tken three times dy for one month. The totl dily dosge provided 150 mg of Cyplexinol, 1500 mg of glucosmine Grin Osteoinductive Protein Complex for Osteorthritis Integrtive Medicine Vol. 11, No. 5 October

3 This rticle is protected by copyright. To shre or copy this rticle, plese visit copyright.com. Use ISSN# X. To subscribe, visit imjournl.com sulfte, nd 1200 mg of chondroitin sulfte. The prticipnts were evluted for the tolerbility of the intervention nd for ny dverse rections ssocited with the supplement contining Cyplexinol plus glucosmine nd chondroitin. If ptient withdrew from the tril, n exit questionnire ws conducted to understnd the reson or cuse. No dditionl prticipnts were dded s replcements. Outcome Mesures VAS Questionnire To ssess the effectiveness of the unique supplement, prticipnts were required to complete the visul nlog scle (VAS) questionnire weekly. The questionnire consisted of prticipnts indicting how they felt regrding their weekly pin by mrking line on the scle (rbitrrily from 0-4). The rw dt ws then trnsformed using sclr function trnsform of y=y [x] K (K=2.5) to llow the dt to be expressed s 10-point scle. Within the trnsition of the dt, there ws no significnt shift in vlues. Tble 1 shows the trnsformed scles on the questionnire. Dt gthered from the VAS questionnires were subjected to sttisticl nlysis using t test with Grphpd PRISM sttisticl nlysis softwre (GrphPd Softwre, Inc, L Joll, CA). One-wy ANOVA ws performed using GrphPd Prism softwre with conservtive post-hoc, Tble 1. VAS Questionnire Scles (Trnsformed) Ctegory Scle Overll pin of 0 = No pin the ffected 2 = Mild pin (25% of the dy) joint 4 = Moderte pin (50% of the dy) 8 = Severe pin (75% of the dy) 10 = Worst possible pin (100% of the dy) Reduction in 0 = No pin the frequency of 2 = Mild pin (25% of the dy) pin 4 = Moderte pin (50% of the dy) 8 = Severe pin (75% of the dy) 10 = Worst possible pin (100% of the dy) Reduction of 0 = Cnnot do ny ctivities pin during 2 = Cn do few ctivitie ctivity (ctivity level) 4 = Cn do some ctivities 8 = Cn do most ctivities 10 = Cn do ll ctivities Reduction in 0 = Incresed pin with ny lifting pin while 2 = Incresed pin with light weight lifting (strength) 4 = Incresed pin with moderte weight 8 = Incresed pin with hevy weight 10 = No pin with hevy lifting Dunnett s Multiple Comprison Test for ech week nd between weeks. The results were evluted ginst the corresponding initil vlues nd the significnt chnge for ech week ws reported. With the mens tht were obtined from the sttisticl ssessment of weeks 0, 1, 2, 3, nd 4 the percent chnge nd percent difference were clculted using the following formts: Percent chnge = (Initil score Week X/Initil) 100; Percent Difference = Initil score Week X/Averge (Initil,Week X) 100 Results Of the 28 rndomized prticipnts tht were enrolled, 23 prticipnts completed the tril. The five prticipnts who did not complete the tril dropped out due to lck of complince; they did not follow up with their helth-cre professionl during the 4-week tril. For the 23 remining prticipnts, complince with the tril s tretment regimen ws excellent. For ll prticipnts who completed the tril, 100% submitted VAS questionnire weekly to their helth-cre professionls. No dverse effects of the tretment were reported by the prticipnts. Following tretment with Cyplexinol plus glucosmine nd chondroitin, prticipnts scores for overll reduction in pin nd frequency of pin from their weekly VAS questionnires showed rpid response to the tretment. This response occurred s quickly s 7 dys fter the supplementtion commenced (Tble 2). As the tretment continued, the overll pin nd the frequency of pin of the ffected joint continued to decrese. By the end of weeks 1, 2, 3, nd 4, the overll reduction in pin from bseline ws 26.5%, 37.7%, 46.7% nd 54.7%, respectively. Similrly the frequency of pin ws reduced by 21.9%, 36.2%, 48.7%, nd 58.8%, respectively. The weekly evlution of both pin nd frequency of pin reveled sttisticlly significnt improvement in both of these prmeters. By the end of the tril, the results of the sttisticl nlysis indicted tht tretment with combintion of Cyplexinol plus glucosmine nd chondroitin significntly reduced overll pin (P <.0001) by 54.7% of the ffected joint (Figure 1). A significnt reduction (P <.0001) in the frequency of pin (58.8%) lso occurred (Figure 2). In ddition, n increse in recretion/ctivity of 41.6% ws reported t the end of week 4 of tretment tht ws the result of the decrese in pin. The increse in recretion/ctivity begn during week 1 nd ws still improving t week 4 (Figure 3). Compred to the bseline vlue, strength lso incresed in the prticipnts by 33% t the end of week 4 (Figure 4). Discussion Osteorthritis is the most common form of rthritis in the United Sttes, ffecting nerly 27 million Americns. 17 This debilitting disese lso results in significnt finncil burden on the helth-cre system nd society, costing the US economy nerly $128 billion per yer in medicl 18 Integrtive Medicine Vol. 11, No. 5 October 2012 Grin Osteoinductive Protein Complex for Osteorthritis

4 This rticle is protected by copyright. To shre or copy this rticle, plese visit copyright.com. Use ISSN# X. To subscribe, visit imjournl.com Tble 2. Men VAS Scores by Ctegory in Cyplexinol Plus Glucosmine nd Chondroitin Supplemented Group Overll Pin (Mens ± SEM) Frequency of Pin (Mens± SEM) Recretion Activity (Mens ± SEM) Strength (Mens ± SEM) Initil 7.07 ± ± ± ± 0.54 Week ± ± ± ± 0.55 Week ± ± ± ± 0.59 Week ± ± ± ± 0.47 Week ± ± ± ± 0.55 Indictes vlues re significntly different from bseline t P <.05. Figure 1. Effect of Cyplexinol Plus Glucosmine nd Chondroitin on Overll Pin, Mesured Weekly Figure 2. Effect of Cyplexinol Plus Glucosmine nd Chondroitin on Reduction in Frequency of Pin, Mesured Weekly Overll Pin The figure shows results for 4 weeks for ffected joints in prticipnts with osteorthritis. Note: The vlues re presented s mens ± stndrd error. Represents vlues significntly different from control t P <.05. The figure shows results for 4 weeks for ffected joints in prticipnts with osteorthritis. Note: The vlues re presented s mens ± stndrd error. Represents vlues significntly different from control t P <.05. Figure 3. Effect of Cyplexinol Plus Glucosmine nd Chondroitin on Increse in Activity Levels, s Mesured by Reduction in Pin During Recretion/Activity Figure 4. Effect of Cyplexinol Plus Glucosmine nd Chondroitin on Increse of Strength, s Mesured by Reduction in Pin During Lifting The figure shows results for 4 weeks for ffected joints in prticipnts with osteorthritis. Note: The vlues re presented s mens ± stndrd error. Represents vlues significntly different from control t P <.05. The figure shows results for 4 weeks for ffected joints in prticipnts with osteorthritis. Note: The vlues re presented s mens ± stndrd error. Represents vlues significntly different from control t P <.05. Grin Osteoinductive Protein Complex for Osteorthritis Integrtive Medicine Vol. 11, No. 5 October

5 This rticle is protected by copyright. To shre or copy this rticle, plese visit copyright.com. Use ISSN# X. To subscribe, visit imjournl.com cre nd indirect expenses, including lost wges nd productivity. 18 The present tril ws designed to evlute the efficcy nd sfety of unique combintion of Cyplexinol, protein complex stimulting bone nd crtilge regenertion tht contins BMPs, plus glucosmine nd chondroitin, s tretment option for osteorthritis. The results of the present preliminry tril support the effectiveness of Cyplexinol plus glucosmine nd chondroitin for the symptomtic tretment of moderte to severe osteorthritis. The results lso indicte tht the combined formultion relieves pin quickly s reported by prticipnts, with reduction of pin in one week. The combintion of Cyplexinol plus glucosmine nd chondroitin hs the dded benefit of voiding the side effects ssocited with long-term use of other osteorthritis tretments such s NSAIDs. 5-7 In the present tril, prticipnts experienced reltively rpid response in the overll pin nd the frequency of pin s evluted by visul nlog scle (VAS) questionnire, with men decrese of 26.5% for overll pin nd 21.9% for frequency of pin fter one week. By the end of the tril period (28 dys), the men response ws pproximtely 54.7% for overll pin nd 48.6% for frequency of pin. These observtions re superior to the responses shown for glucosmine nd chondroitin in previous clinicl investigtions. 8,9 The mesures of subjective symptoms of osteorthritis, such s pin nd stiffness, nd the wide vrition in individul ptient s perceptions of these symptoms, result in complex reltionships tht cn be difficult to elucidte from the reporting of men tretment effects in clinicl trils. These mesures my fil to dequtely describe the potentil benefits to the individul ptient In the present tril, VAS ws used. Visul nlog nd ctegoricl scles hve been reported to be effective in determining verge pin due to osteorthritis. 23 Compred to the conventionl tretment with products such s glucosmine nd chondroitin, the results of this tril lso suggest tht n dditionl mechnism of ction my be t work. The rpid onset of ction nd the high percentge of prticipnts with clinicl improvement from dministrtion of Cyplexinol plus glucosmine nd chondroitin, my indicte n nti-inflmmtory process due to the Cyplexinol protein complex. The BMPs within Cyplexinol hve been well documented within the medicl nd scientific literture to exhibit not only bone nd crtilge regenertive properties but nti-inflmmtory properties s well. 24 The regenertion of tissue could lso influence the degree of pin by reversing the degenertive process. The onset of heling nd diminution of inflmmtory processes lso pper to ffect the increse of proinflmmtory cytokines within the ffected tissues. These cytokines hve been linked to the destruction of crtilge in osteorthritis by ctivting the Interleukin-1 (IL-1) pthwy nd its downstrem components. 15,25 Excessive levels of IL-1 in the synovil tissue hve been ssocited with greter ttrition of bone nd crtilge. IL-1 is proinflmmtory cytokine tht binds to the IL-1 receptor type 1, leding to the ctivtion of the NF-kb trnscription fctor nd expression of mtrix metlloproteinse. 14 To restore the joint dmge due to osteorthritis, strtegies exploring the consequences of blocking or stopping the trgets of these cytokines re required. In this regrd, the results of this present tril following tretment with Cyplexinol, which contins BMPs, plus glucosmine nd chondroitin, hve shown promise s nturl lterntive. The regenertion of crtilge nd bone tissue my, therefore, hve direct effect on inflmmtion through interction with inflmmtory cytokines. The progression of osteorthritis hs been shown to depend on the degrdtion of type II collgen nd proteoglycn molecules. 26,27 Interstitil collgenses, such s mtrix metlloproteinse or MMP-1, MMP-8, nd MMP-13 tht re upregulted by IL-1, re reported to degrde type II collgen in crtilge. Among these collgenses, elevted levels of MMP-1 nd MMP-13 hve been observed in rthritic tissues. The TGF-b superfmily of proteins, such s BMP-2 nd TGF-b, hs n immunosuppressive effect ginst the IL-1 pthwy nd protective effect ginst collgen degrdtion by inhibiting MMP-1 nd MMP-13 expression. 25,28,29 In vivo studies hve shown tht BMP-2 nd TGF-bet induce proteoglycn synthesis. 30,31 The mechnism of ction of the constituents of the unique complex used in the present tril, nd prticulrly tht of Cyplexinol, such s BMP-2 nd TGF-b, ppers to be relted to the induction of synthesis of proteoglycn molecules, resulting in the rrest of the progression of osteorthritis s well s recovery. In spite of the present preliminry tril s limittions, such s the fct tht it ws open-lbeled, hd smll smple size, nd used VAS, its results suggest tht orl dministrtion to subjects suffering from osteorthritis of n osteoinductive protein complex, Cyplexinol, plus glucosmine nd chondroitin, reduces overll pin nd frequency of pin. The results of the present tril, in conjunction with previously published dt, indicte new prdigm in scientists understnding of the pthogenesis of osteorthritis nd suggest reltionship between exogenous BMP-signlling vi orl dministrtion nd joint function nd repir. As such, the BMPs in Cyplexinol my provide importnt new tools in the clinicl mngement of moderte to severe osteorthritis. In conclusion, tretment with combintion of Cyplexinol plus glucosmine nd chondroitin ws found to be effective for people with moderte to severe, joint pin nd stiffness. 20 Integrtive Medicine Vol. 11, No. 5 October 2012 Grin Osteoinductive Protein Complex for Osteorthritis

6 This rticle is protected by copyright. To shre or copy this rticle, plese visit copyright.com. Use ISSN# X. To subscribe, visit imjournl.com References 1. Felson DT, Zhng Y. An updte on the epidemiology of knee nd hip osteorthritis with view to prevention. Arthritis Rheum. 1998;41(8): Iss SN, Shrm L. Epidemiology of osteorthritis: n updte. Curr Rheumtol Rep. 2006;8(1): Lwrence RC, Felson DT, Helmick CG, et l. Estimtes of the prevlence of rthritis nd other rheumtic conditions in the United Sttes. Prt II. Arthritis Rheum. 2008;58(1): Hochberg MC, Altmn RD, Brndt KD, et l. Guidelines for the medicl mngement of osteorthritis. II. Osteorthritis of the knee. Americn College of Rheumtology. Arthritis Rheum. 1995;38(11): Wolfe MM, Lichtenstein DR, Singh G. Gstrointestinl toxicity of nonsteroidl nti-inflmmtory drugs. N Engl J Med. 1999;340(24): Tmblyn R, Berkson L, Duphinee WD, et l. Unnecessry prescribing of NSAIDs nd the mngement of NSAID-relted gstropthy in medicl prctice. Ann Intern Med. 1997;127(6): Smlley WE, Ry WA, Dugherty JR, Griffin MR. Nonsteroidl nti-inflmmtory drugs nd the incidence of hospitliztions for peptic ulcer disese in elderly persons. Am J Epidemiol. 1995;141(6): Clegg DO, Red DJ, Hrris CL, et l. Glucosmine, chondroitin sulfte, nd the two in combintion for pinful knee osteorthritis. N Engl J Med. 2006;354(8): Herrero-Beumont G, Ivorr JA, Del Crmen Trbdo M, et l. Glucosmine sulfte in the tretment of knee osteorthritis symptoms: rndomized, double-blind, plcebo-controlled study using cetminophen s side comprtor. Arthritis Rheum. 2007;56(2): Glnsbeek HL, vn Beuningen HM, Vitters EL, vn der Krn PM, vn den Berg WB. Stimultion of rticulr crtilge repir in estblished rthritis by locl dministrtion of trnsforming growth fctor-bet into murine knee joints. Lb Invest. 1998;78(2): Pfeilschifter J, Oechsner M, Numnn A, Gronwld RG, Minne HW, Ziegler R. Stimultion of bone mtrix pposition in vitro by locl growth fctors: comprison between insulin-like growth fctor I, pltelet-derived growth fctor, nd trnsforming growth fctor bet. Endocrinology. 1990;127(1): Brmlge CP, Häupl T, Kps C, et l. Decrese in expression of bone morphogenetic proteins 4 nd 5 in synovil tissue of ptients with osteorthritis nd rheumtoid rthritis. Arthritis Res. 2006;8(3):R Kuo AC, Rodrigo JJ, Reddi AH, Curtiss S, Grotkopp E, Chiu M. Microfrcture nd bone morphogenetic protein 7 (BMP-7) synergisticlly stimulte rticulr crtilge repir. Osteorthritis Crtilge. 2006;14(11): Ronzière MC, Aubert-Foucher E, Gouttenoire J, Bernud J, Herbge D, Mllein-Gerin F. Integrin lph1bet1 medites collgen induction of MMP- 13 expression in MC615 chondrocytes. Biochim Biophys Act. 2005;1746(1): Lee MJ, Yng CW, Jin DC, Chng YS, Bng BK, Kim YS. Bone morphogenetic protein-7 inhibits constitutive nd interleukin-1 bet induced monocyte chemo ttrctnt protein-1 expression in humn mesngil cells: role for JNK/AP-1 pthwy. J Immunol. 2003;170(5): Cmpbell WI, Lewis S. Visul nlogue mesurement of pin. Ulster Med J. 1990;59(2): Helmick C, Felson D, Lwrence R, et l. Estimtes of the prevlence of rthritis nd other rheumtic conditions in the United Sttes. Prt I. Arthritis Rheum. 2008;58(1): Center for Disese nd Control. Ntionl nd stte medicl expenditures nd lost ernings ttributble to rthritis nd other rheumtic conditions--united Sttes, MMWR MorbMortl Wkly Rep. 2007;56(1): Lötsch J, Geisslinger G. Current evidence for genetic modultion of the response to nlgesics. Pin. 2006;121(1-2): McQuy H, Moore A. Utility of clinicl tril results for clinicl prctice. Eur J Pin. 2007;11(2): Moore RA, Moore OA, Derry S, McQuy HJ. Numbers needed to tret clculted from responder rtes give better indiction of efficcy in osteorthritis trils thn men pin scores. Arthritis Res Ther. 2008;10(2):R Tubch F, Rvud P, Girudeu B. Mnging osteorthritis of the knee: conclusions bout use of NSAIDs re misleding. BMJ. 2205;330(7492): Averbuch M, Ktzper M. Assessment of visul nlog versus ctegoricl scle for mesurement of osteorthritis pin. J Clin Phrmcol. 2004;44(4): Chubinsky S, Hkimiyn A, Pcione C, et l. Synergistic effect of IGF-1 nd OP-1 on mtrix formtion by norml nd OA chondrocytes cultured in lginte beds. Osteorthritis Crtilge. 2007;15(4): Aigner T, Soeder S, Hg J. IL-1bet nd BMPs interctive plyers of crtilge mtrix degrdtion nd regenertion. Eur Cell Mter Oct 26;12: Hrdy MM, Seibert K, Mnning PT, et l. Cyclooxygense 2-dependent prostglndin E2 modultes crtilge proteoglycn degrdtion in humn osteorthritis explnts. Arthritis Rheum. 2002;46(7): Vincenti MP, Brinckerhoff CE. Trnscriptionl regultion of collgense (MMP-1, MMP-13) genes in rthritis: integrtion of complex signling pthwys for the recruitment of gene-specific trnscription fctors. Arthritis Res. 2002;4(3): Tkiguchi T, Kobvshi M, Suzuki R, et l. Recombinnt humn bone morphogenetic protein-2 stimultes osteoblst differentition nd suppresses mtrix metlloproteinse-1 production in humn bone cells isolted from mndibule. J Periodontl Res. 1998;33(8): Chen H, Li D, Sldeen T, Meht JL. TGF-bet 1 ttenutes myocrdil ischemi- reperfusion injury vi inhibition of upregultion of MMP-1. Am J Physiol Hert Circ Physiol. 2003;284(5):H1612-H Glnsbeek HL, vn Beuningen HM, Vitters EL, Morris EA, vn der Krn PM, vn den Berg WB. Bone morphogenetic protein 2 stimultes rticulr crtilge proteoglycn synthesis in vivo but does not counterct interleukin- 1lph effects on proteoglycn synthesis nd content. Arthritis Rheum. 1997;40(6): Poleni PE, Binchi A, Etienne S, et l. Agonists of peroxisome prolifertorsctivted receptors (PPAR) lph, bet/delt or gmm reduce trnsforming growth fctor (TGF)-bet-induced proteoglycns production in chondrocytes. Osteorthritis Crtilge. 2007;15(5): Grin Osteoinductive Protein Complex for Osteorthritis Integrtive Medicine Vol. 11, No. 5 October