Integrative cartilage repair: Inhibition by β‐aminopropionitrile

Ahsan, Tabassum; Lottman, Lisa M.; Harwood, Frederick L.; Amiel, David; Sah, Robert L.

doi:10.1002/jor.1100170610

Cited by 68 publications

(57 citation statements)

References 45 publications

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“…Given that blocking the MMPs, and thus the degradation of the extracellular matrix, was not sufficient to reverse the full effects of IL-1, perhaps promoting the synthesis of new extracellular matrix components may help to enhance the integrative repair process. In a cartilage repair model system, the strength of repair is positively correlated with collagen deposition [17] and cross-linking [2,18]. Thus, factors that increase collagen synthesis and decrease MMP activity likely would benefit meniscal repair.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Matrix Metalloproteinases Enhances In Vitro Repair of the Meniscus

McNulty

Weinberg

Guilak

2008

Clin Orthop Relat Res

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Damage or injury of the meniscus is associated with onset and progression of knee osteoarthritis (OA). The intrinsic repair capacity of the meniscus is inhibited by inflammatory cytokines, such as interleukin-1 (IL-1). Using an in vitro meniscal repair model system, we examined the hypothesis that inhibition of matrix metalloproteinases (MMPs) in the presence of IL-1 will enhance repair of meniscal lesions. Integrative repair of the meniscus was examined between two concentric explants cultured with IL-1 and various MMP inhibitors for 14 days. Throughout the culture period, we assessed total specific MMP activity in the media. At harvest, biomechanical testing to assess the strength of repair and histologic staining were performed. IL-1 decreased the shear strength of repair, as compared with control explants. In the presence of IL-1, the broad-spectrum MMP inhibitor GM 6001 decreased the MMP activity in the media, increased the shear strength of repair, and enhanced tissue repair in the interface. However, individual MMP inhibitors did not alter the shear strength of repair in either the presence or absence of IL-1. These findings suggest IL-1 may inhibit meniscal repair through upregulation of MMPs, but inhibition of multiple MMPs may be necessary to promote integrative meniscal repair.

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Section: Resultsmentioning

confidence: 99%

Inhibition of Matrix Metalloproteinases Enhances In Vitro Repair of the Meniscus

McNulty

Weinberg

Guilak

2008

Clin Orthop Relat Res

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“…[62][63][64] Glycation in solution may also enhance integration with the surrounding tissue due to accumulation of intermediates that may be able to crosslink to native tissue and to provide an increase in collagen crosslinking to foster tissue regeneration in vivo.…”

Section: Discussionmentioning

confidence: 99%

Non‐enzymatic glycation of chondrocyte‐seeded collagen gels for cartilage tissue engineering

Roy¹,

Boskey²,

Bonassar³

2008

Journal Orthopaedic Research

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Collagen glycated with ribose (250 mM) in solution (pre-glycation) and as a gel (post-glycation) was seeded with chondrocytes and the effects of glycation on chondrocyte matrix assembly in culture were determined. Pre-glycation enhanced GAG accumulation significantly over controls at both 2 and 4 weeks (p < 0.05), although at both time points there were no statistical differences in cell number between pre-glycated and control gels. The increased proteoglycan accumulation was shown to be in part due to significantly increased GAG retention by the pre-glycated constructs (p < 0.05). Total collagen content in these pre-glycated gels was also significantly higher than unglycated gels at 4 weeks (p < 0.05). With post-glycation of collagen gels, chondrocyte number and GAG accumulation were all significantly lower than controls (p < 0.05). Post-glycation also inhibited GAG retention by the constructs (p < 0.05). Given these results, pre-glycation may be an improved processing method for collagen gels for tissue engineering techniques. ß

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“…Studies of cartilage explants designed to investigate integrative repair in vitro, show that treatment with BAPN, a specific lysyl oxidase enzyme activity inhibitor (4), results in increased collagen extractablility with a concurrent reduction of dihydroxylysinonorleucine cross-links. BAPN treated explants also display markedly inhibited functional integrative cartilage repair in vitro (43). Cartilage explants pretreated with BAPN, followed by its withdrawal before a period of integrative repair resulted in an ultimate increase in integrative strength of the explant (44).…”

Section: Volume 286 • Number 2 • January 14 2011mentioning

confidence: 93%

Lysyl Oxidase-like-2 (LOXL2) Is a Major Isoform in Chondrocytes and Is Critically Required for Differentiation

Iftikhar¹,

Hurtado²,

Bais

et al. 2011

Journal of Biological Chemistry

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The lysyl oxidase family is made up of five members: lysyl oxidase (LOX) and lysyl oxidase-like 1-4 (LOXL1-LOXL4). All members share conserved C-terminal catalytic domains that provide for lysyl oxidase or lysyl oxidase-like enzyme activity; and more divergent propeptide regions. LOX family enzyme activities catalyze the final enzymatic conversion required for the formation of normal biosynthetic collagen and elastin cross-links. The importance of lysyl oxidase enzyme activity to normal bone development has long been appreciated, but regulation and roles for specific LOX isoforms in bone formation in vivo is largely unexplored. Fracture healing recapitulates aspects of endochondral bone development. The present study first investigated the expression of all LOX isoforms in fracture healing. A remarkable coincidence of LOXL2 expression with the chondrogenic phase of fracture healing was found, prompting more detailed analyses of LOXL2 expression in normal growth plates, and LOXL2 expression and function in developing ATDC5 chondrogenic cells. Data show that LOXL2 is expressed by pre-hypertrophic and hypertrophic chondrocytes in vivo, and that LOXL2 expression is regulated in vitro as a function of chondrocyte differentiation. Moreover, LOXL2 knockdown studies in vitro show that LOXL2 expression is required for ATDC5 chondrocyte cell line differentiation through regulation of SNAIL and SOX9, important transcription factors that control chondrocyte differentiation. Taken together, data provide evidence that LOXL2, like LOX, is a multifunctional protein. LOXL2 promotes chondrocyte differentiation by mechanisms that are likely to include roles as both a regulator and an effector of chondrocyte differentiation.The lysyl oxidase family is made up of five members: lysyl oxidase (LOX) 3 and lysyl oxidase-like 1-4 (LOXL1-LOXL4)(1). All five members share a conserved C-terminal catalytic domain that provides for lysyl oxidase or lysyl oxidase-like enzyme activity, and more divergent propeptide regions. LOX family enzyme activities catalyze the final enzymatic conversion required for the subsequent formation of normal lysinederived biosynthetic cross-links found in collagens and elastin (2). The importance of lysyl oxidase enzyme activity to normal bone development has long been known, and is based in part on studies in which enzyme activities are inhibited by lathyrogens in vivo (3), including ␤-aminopropionitrile, a potent inhibitor of LOX and LOX isoform activity (4). The LOX family can be subdivided into two subgroups. Although all members have similarities in the catalytic C-terminal region, LOX and LOXL1 are more closely related to each other than they are to LOXL2-LOXL4. Moreover, the pro-peptide regions of LOX and LOXL1 have very little similarity to each other and no similarity to LOXL2-LOXL4. The pro-regions of LOXL2-LOXL4 each contain four scavenger receptor cysteine-rich (SRCR) domains whose functions are likely to depend on interactions with other proteins (1). The pro-regions of all LOX family members may have...

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Integrative cartilage repair: Inhibition by β‐aminopropionitrile

Cited by 68 publications

References 45 publications

Inhibition of Matrix Metalloproteinases Enhances In Vitro Repair of the Meniscus

Inhibition of Matrix Metalloproteinases Enhances In Vitro Repair of the Meniscus

Non‐enzymatic glycation of chondrocyte‐seeded collagen gels for cartilage tissue engineering

Lysyl Oxidase-like-2 (LOXL2) Is a Major Isoform in Chondrocytes and Is Critically Required for Differentiation

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