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The effect of a vitamin B-6 antagonist, 4-deoxypyridoxine, on the cross-linking of collagen in the developing chick embryo.

ABSTRACT: The vitamin B-6 antimetabolite 4-deoxypyridoxine, when injected into 13-day chick embryos, has the effect of increasing the amount of collagen solubilized from the leg bones by buffered saline solutions, 24 h after the injection. This effect is similar to, but less marked than, that produced by the administration of the lathyrogen beta-amino-propionitrile. Since that fraction of the total collagen which is solubilized by saline represents the least-cross-linked pool, it is concluded that 4-deoxypyridoxine is a lathyrogen, decreasing the cross-linking in the developing embryo, and confirming the importance of vitamin B-6 in that process. Lysyl oxidase, the cross-linking enzyme, was measured in extracts made from the epiphysial cartilages of embryos 24 h after the injection of either 4-deoxypyridoxine or beta-aminopropionitrile. The injection of 5 mg of beta-aminopropionitrile causes the lysyl oxidase activity to fall to 61% of that of saline-injected controls; after treatment with 4-deoxypyridoxine, the activity is 74% of the control value. In the latter case, full activity is not restored to the extracts by preincubation with pyridoxal phosphate. The results are discussed in relation to the early development of the connective tissues.

SUBMITTER: Bird TA

PROVIDER: S-EPMC1154271 | biostudies-other | 1983 Mar

REPOSITORIES: biostudies-other

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Project description:The inability to recapitulate native tissue biomechanics, especially tensile properties, hinders progress in regenerative medicine. To address this problem, strategies have focused on enhancing collagen production. However, manipulating collagen cross-links, ubiquitous throughout all tissues and conferring mechanical integrity, has been underinvestigated. A series of studies examined the effects of lysyl oxidase (LOX), the enzyme responsible for the formation of collagen cross-links. Hypoxia-induced endogenous LOX was applied in multiple musculoskeletal tissues (i.e., cartilage, meniscus, tendons, ligaments). Results of these studies showed that both native and engineered tissues are enhanced by invoking a mechanism of hypoxia-induced pyridinoline (PYR) cross-links via intermediaries like LOX. Hypoxia was shown to enhance PYR cross-linking 1.4- to 6.4-fold and, concomitantly, to increase the tensile properties of collagen-rich tissues 1.3- to 2.2-fold. Direct administration of exogenous LOX was applied in native cartilage and neocartilage generated using a scaffold-free, self-assembling process of primary chondrocytes. Exogenous LOX was found to enhance native tissue tensile properties 1.9-fold. LOX concentration- and time-dependent increases in PYR content (∼ 16-fold compared with controls) and tensile properties (approximately fivefold compared with controls) of neocartilage were also detected, resulting in properties on par with native tissue. Finally, in vivo subcutaneous implantation of LOX-treated neocartilage in nude mice promoted further maturation of the neotissue, enhancing tensile and PYR content approximately threefold and 14-fold, respectively, compared with in vitro controls. Collectively, these results provide the first report, to our knowledge, of endogenous (hypoxia-induced) and exogenous LOX applications for promoting collagen cross-linking and improving the tensile properties of a spectrum of native and engineered tissues both in vitro and in vivo.

Project description:Synovial joints are among the most important structures that give us complex motor abilities as humans. Degenerative joint diseases, such as arthritis, cause loss of normal joint functioning and affect over 40 million people in the USA and approximately 350 million people worldwide. Therapies based on regenerative medicine hold the promise of effectively repairing or replacing damaged joints permanently. Here, for the first time, we introduce a model for synovial joint regeneration utilizing the chick embryo. In this model, a block of tissue that contains the prospective elbow is excised, leaving a window with strips of anterior and posterior tissue intact (window excision, WE). In contrast, we also slice out the same area containing the elbow and the distal piece of the limb is pinned back onto the stump (slice excision, SE). Interestingly, when the elbow is removed via WE, regeneration of the joint takes place, whereas the elbow joint does not regenerate following SE. In order to investigate whether the regeneration response recapitulates the developmental program of forming joints, we used GDF-5 and Autotaxin (Atx) as joint tissue specific markers, and Sox-9 and Col-9 as cartilage markers for in situ hybridization on sections at different time points after WE and SE surgeries. Re-expression of GDF-5 and Atx is observed in the WE samples by 60h after surgery. In contrast, the majority of the samples that underwent SE surgery did not express GDF-5 and Atx. Also, in SE fusion of cartilage elements takes place and the joint interzone does not form. This is indicated by continuous Col-9 expression in SE limbs, whereas Col-9 is downregulated at the joint interzone in the regenerating WE samples. This order and pattern of gene expression observed in regenerates is similar to the development of a joint suggesting that regeneration recapitulates development at the molecular level. This model defines some of the conditions required for inducing joint regeneration in an otherwise nonregenerating environment. This knowledge can be useful for designing new therapeutic approaches for joint loss or for conditions affecting joint integrity in humans.

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The effect of a vitamin B-6 antagonist, 4-deoxypyridoxine, on the cross-linking of collagen in the developing chick embryo.

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