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Developments in the scientific understanding of osteoarthritis

Abramson, Steven B; Attur, Mukundan
Osteoarthritis is often a progressive and disabling disease, which occurs in the setting of a variety of risk factors--such as advancing age, obesity, and trauma--that conspire to incite a cascade of pathophysiologic events within joint tissues. An important emerging theme in osteoarthritis is a broadening of focus from a disease of cartilage to one of the 'whole joint'. The synovium, bone, and cartilage are each involved in pathologic processes that lead to progressive joint degeneration. Additional themes that have emerged over the past decade are novel mechanisms of cartilage degradation and repair, the relationship between biomechanics and biochemical pathways, the importance of inflammation, and the role played by genetics. In this review we summarize current scientific understanding of osteoarthritis and examine the pathobiologic mechanisms that contribute to progressive disease
PMCID:2714096
PMID: 19519925
ISSN: 1478-6362
CID: 101117

PGE2 differentially regulates expression of chondrocyte markers during chondrogenesis of human bone marrow derived MSCs [Meeting Abstract]

Palmer G.; Al-Mussawir H.; Attur M.; Abramson S.B.
Purpose: A necessary step for the successful regeneration of cartilage lesions using stem cell-based therapies is the controlled differentiation of progenitor cells into a stable articular chondrocyte phenotype. Prostaglandin E2 (PGE2) has been shown to have an important role in both fracture healing and chondrocyte maturation during endochondral bone formation. This study investigates the effects of PGE2 on chondrocyte differentiation of adult, human mesenchymal stem cells (MSCs). Methods: Bone marrow-derived MSCs were isolated from the discarded tissues of patients undergoing hip replacement surgery. Chondrogenesis was induced by seeding MSCs in serum-free aggregate cultures supplemented with dexamethasone (10-7 M) and TGF-b1 (10 ng/ml). At various time points, RNA was extracted for gene expression analysis by semi-quantitative RT-PCR. PGE2 levels were determined by RIA. Results: Gene expression analysis of 4 patient samples revealed an order-of-magnitude increase in chondrogenic markers, col II, col X, MMP-13 and AP. In each case, expression was elevated by day 7 and persisted for the duration of the assay (21 d). To determine the effects of PGE2, aggregates were cocultured in the presence of exogenous PGE2 (10-6 M) and expression of chondrocyte markers determined after 14 d. PGE2 increased expression of col II (65%) and decreased expression of hypertrophic markers, col X (20%), MMP-13 (32 %) and AP (55%). Consistent with these observations, histological examination of treated aggregates after 21 d revealed fewer enlarged, hypertrophic chondrocytes following PGE2 treatment compared to control cultures. In aggregate cultures, PGE2 secretion was inhibited by the selective cox-2 inhibitor, celecoxib, approximately 50%, while cox-1 inhibition by treatment with SC-560 had no effect. Accordingly, celecoxib treatment of chondrogenic aggregates for 7 d decreased expression of sox-9 (80%) and col II (97%) compared non-treated controls. Cox-2 inhibition also increased expression of hypertrophic markers. Celecoxib treatment increased col X (95%) and AP (150%), but had no effect on MMP-13 levels. After 21 d, aggregates treated with celecoxib exhibited greater numbers of hypertrophic chondrocytes, and a modest decrease in proteoglycan staining. These findings suggest that cox-2 derived PGE2 has the capacity modulate chondrocyte differentiation of MSCs via differential regulation of chondrocyte marker genes. Conclusion: PGE2, via upregulation of type II collagen, or inhibition of chondrocyte hypertrophy, has the capacity to regulate chondrocyte phenotype during in vitro chondrogenesis of hMSCs. Further characterization should uncover novel PGE2 pathways that can be exploited to modulate chondrocyte phenotype for tissue regeneration therapies
EMBASE:70374200
ISSN: 0004-3591
CID: 130337

Pathogenesis of osteoarthritis

Chapter by: Di Cesare PE; Samuels J; Abramson SB
in: Kelley's textbook of rheumatology by Firestine GS; Kelley WN [Eds]
Philadelphia, PA : Saunders/Elsevier, 2009
pp. ?-?
ISBN: 1416032851
CID: 4812

Variable X-ray beam angulation improves quality of medial tibial plateau alignment in fixed-flexion knee radiographs of osteoarthritis (OA) patients [Meeting Abstract]

Alapati K.; Belitskaya-Levy I.; Schweitzer M.; Shabshin N.; Samuels J.; Abramson S.B.; Krasnokutsky S.
Purpose: To assess whether variability in caudal X-ray beam angulation (CBA) improves alignment of the medial tibial plateau (MTP) versus a fixed 10degree CBA, using non-fluoroscopic fixed-flexion knee radiographs. Methods: 133 subjects with knee OA underwent fixed-flexion AP X-ray examinations as part of a longitudinal study. We performed a cross sectional substudy in which 90 subjects were imaged with a 10degree CBA (Method 1) and 43 subjects were imaged using different CBAs (choosing from 5degree, 10degree, 15degree) determined by a trained radiology technician, depending on MTP alignment assessed in real time (Method 2). After reading a blinded training set of radiographs, an experienced radiologist, who was blinded to patients and method used, read the x-rays for MTP alignment quality using a 1-5 scale (1, 2=good, 3=acceptable, 4= poor, 5= unacceptable), and for Kellgren-Lawrence (KL) grade. Results: Method 1 subjects (10degree angulation): MTP alignment quality was scored as good or acceptable 62% and 69% of the time for the right and left knees, respectively. Method 2 subjects (variable angulation): Variable angulation resulted in good or acceptable MTP alignment quality on at least one x-ray 86% and 88% of the time for right and left knees, respectively. When CBA was changed, MTP alignment quality changed 84% of the time for the right knee and 77% of the time for the left knee in subjects who had at least 2 radiographs (n=43). The KL grade changed 28% and 46% of the time in the right and left knees, respectively, when MTP alignment quality changed in the same knee. The KL grade changed 38% and 36% of the time in the right and left knees, respectively, when there was no change in MTP alignment quality but there was a change in CBA. A change in CBA resulted in MTP alignment quality change in bilateral knees 66% of the time, of which this change was in the same direction (improved vs worsened) 86% of the time. Using a CBA of 10degree resulted in improved (over other angulations) MTP alignment quality 53% and 50% of the time for the right and left knees, respectively. Using a CBA of 10degree resulted in worsened MTP alignment 33% and 22% of the time for right and left knees, respectively. Conclusion: While fixed 10degree CBA in fixed-flexion radiographs results in acceptable or good MTP alignment quality the majority of the time, variable CBA improves this frequency in knee OA subjects. Changes in CBA often change the MTP alignment quality, usually in the same direction in both knees, and sometimes change the KL grade. More studies are needed to determine the optimal CBA for non-fluoroscopic fixed-flexion protocols and all radiographic knee OA studies should report the specific techniques used, including CBA
EMBASE:70374890
ISSN: 0004-3591
CID: 130350

Inhibition of ADAMTS-7 and ADAMTS-12 degradation of cartilage oligomeric matrix protein by alpha-2-macroglobulin

Luan, Y; Kong, L; Howell, D R; Ilalov, K; Fajardo, M; Bai, X-H; Di Cesare, P E; Goldring, M B; Abramson, S B; Liu, C-J
OBJECTIVE: As we previously reported, ADAMTS-7 and ADAMTS-12, two members of ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) family, degrade cartilage oligomeric matrix protein (COMP) in vitro and are significantly induced in the cartilage and synovium of arthritic patients [Liu CJ, Kong W, Ilalov K, Yu S, Xu K, Prazak L, et al. ADAMTS-7: a metalloproteinase that directly binds to and degrades cartilage oligomeric matrix protein. FASEB J 2006;20(7):988-90; Liu CJ, Kong W, Xu K, Luan Y, Ilalov K, Sehgal B, et al. ADAMTS-12 associates with and degrades cartilage oligomeric matrix protein. J Biol Chem 2006;281(23):15800-8]. The purpose of this study was to determine (1) whether cleavage activity of ADAMTS-7 and ADAMTS-12 of COMP are associated with COMP degradation in osteoarthritis (OA); (2) whether alpha-2-macroglobulin (a(2)M) is a novel substrate for ADAMTS-7 and ADAMTS-12; and (3) whether a(2)M inhibits ADAMTS-7 or ADAMTS-12 cleavage of COMP. METHODS: An in vitro digestion assay was used to examine the degradation of COMP by ADAMTS-7 and ADAMTS-12 in the cartilage of OA patients; in cartilage explants incubated with tumor necrosis factor-alpha (TNF-alpha) or interleukin-1-beta (IL-1beta) with or without blocking antibodies; and in human chondrocytes treated with specific small interfering RNA (siRNA) to knockdown ADAMTS-7 or/and ADAMTS-12. Digestion of a(2)M by ADAMTS-7 and ADAMTS-12 in vitro and the inhibition of ADAMTS-7 or ADAMTS-12-mediated digestion of COMP by a(2)M were also analyzed. RESULTS: The molecular mass of the COMP fragments produced by either ADAMTS-7 or ADAMTS-12 were similar to those observed in OA patients. Specific blocking antibodies against ADAMTS-7 and ADAMTS-12 dramatically inhibited TNF-alpha- or IL-1beta-induced COMP degradation in the cultured cartilage explants. The suppression of ADAMTS-7 or ADAMTS-12 expression by siRNA silencing in the human chondrocytes also prevented TNF-alpha- or IL-1beta-induced COMP degradation. Both ADAMTS-7 and ADAMTS-12 were able to cleave a(2)M, giving rise to 180- and 105-kDa cleavage products, respectively. Furthermore, a(2)M inhibited both ADAMTS-7- and ADAMTS-12-mediated COMP degradation in a concentration (or dose)-dependent manner. CONCLUSION: Our observations demonstrate the importance of COMP degradation by ADAMTS-7 and ADAMTS-12 in vivo. Furthermore, a(2)M is a novel substrate for ADAMTS-7 and ADAMTS-12. More significantly, a(2)M represents the first endogenous inhibitor of ADAMTS-7 and ADAMTS-12
PMCID:2574789
PMID: 18485748
ISSN: 1063-4584
CID: 80346

Prostaglandin E2 exerts catabolic effects in osteoarthritis cartilage: evidence for signaling via the EP4 receptor

Attur, Mukundan; Al-Mussawir, Hayf E; Patel, Jyoti; Kitay, Alison; Dave, Mandar; Palmer, Glyn; Pillinger, Michael H; Abramson, Steven B
Elevated levels of PGE(2) have been reported in synovial fluid and cartilage from patients with osteoarthritis (OA). However, the functions of PGE(2) in cartilage metabolism have not previously been studied in detail. To do so, we cultured cartilage explants, obtained from patients undergoing knee replacement surgery for advanced OA, with PGE(2) (0.1-10 muM). PGE(2) inhibited proteoglycan synthesis in a dose-dependent manner (maximum 25% inhibition (p < 0.01)). PGE(2) also induced collagen degradation, in a manner inhibitable by the matrix metalloproteinase (MMP) inhibitor ilomastat. PGE(2) inhibited spontaneous MMP-1, but augmented MMP-13 secretion by OA cartilage explant cultures. PCR analysis of OA chondrocytes treated with PGE(2) with or without IL-1 revealed that IL-1-induced MMP-13 expression was augmented by PGE(2) and significantly inhibited by the cycolooygenase 2 selective inhibitor celecoxib. Conversely, MMP-1 expression was inhibited by PGE(2), while celecoxib enhanced both spontaneous and IL-1-induced expression. IL-1 induction of aggrecanase 5 (ADAMTS-5), but not ADAMTS-4, was also enhanced by PGE(2) (10 muM) and reversed by celecoxib (2 muM). Quantitative PCR screening of nondiseased and end-stage human knee OA articular cartilage specimens revealed that the PGE(2) receptor EP4 was up-regulated in OA cartilage. Moreover, blocking the EP4 receptor (EP4 antagonist, AH23848) mimicked celecoxib by inhibiting MMP-13, ADAMST-5 expression, and proteoglycan degradation. These results suggest that PGE(2) inhibits proteoglycan synthesis and stimulates matrix degradation in OA chondrocytes via the EP4 receptor. Targeting EP4, rather than cyclooxygenase 2, could represent a future strategy for OA disease modification
PMID: 18802112
ISSN: 1550-6606
CID: 91441

F-spondin, a neuroregulatory protein, is upregulated in human and surgically-induced osteoarthritis: Evidence for regulation of cartilage metabolism via latent tgf-b1 activation [Meeting Abstract]

Attur, M; Palmer, G; Al-Mussawir, HE; Rifkin, DB; Teixeira, CC; Appleton, CTG; Beier, F; Abramson, SB
ISI:000259244202470
ISSN: 0004-3591
CID: 88578

The use of musculoskeletal ultrasound: Rheumatologists in the US [Meeting Abstract]

Samuels, J; Abramson, SB
ISI:000259244201080
ISSN: 0004-3591
CID: 88551

The progeria-associated protein lamin a is upregulated in osteoarthritis: Evidence for premature chondrocyte senescence [Meeting Abstract]

Ben-Artzi, A; Attur, M; Dave, M; Al-Mussawir, H; Palmer, G; Abramson, SB
ISI:000259244202418
ISSN: 0004-3591
CID: 88576

Synovial but not cartilage volumes on MRI predict radiographic severity of knee Osteoarthritis (OA) [Meeting Abstract]

Krasnokutsky, S; Samuels, J; Attur, M; Regatte, R; Belitskaya-Levy, I; Babb, J; Rosenthal, P; Al-Mussawir, H; Abellana, V; Greenberg, J; Schweitzer, M; Abramson, SB
ISI:000259244202457
ISSN: 0004-3591
CID: 88577