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PubMed1993

Type II collagen during cartilage and corneal development: immunohistochemical analysis with an anti-telopeptide antibody.

We have examined the pattern of immunoreactivity of a monoclonal antibody, II-5B2, with specificity for an epitope which resides within the NH2-terminal extension peptide (telopeptide) of the avian type II collagen molecule. This epitope is available in regions of matrix where de novo synthesis of the molecule is ongoing, but not where synthesis has ceased and maturation and crosslink formation have occurred. Within the cartilaginous growth plate, the epitope disappears from the matrix soon after the chondrocytes become hypertrophic; within the cornea, the epitope disappears subjacent to the epithelium. The II-5B2 epitope is not made available by a variety of procedures shown to remove potentially masking substances and to disrupt fibrillar organization. It is rendered available, however, when covalent crosslink formation between collagen molecules is blocked through administration of beta-aminopropionitrile or penicillamine. In contrast, the epitope of another monoclonal antibody against type II collagen, II-II6B3, which resides in the triple-helical domain of the molecule, in cartilage is present throughout the growth plate including the hypertrophic zone, and in cornea extends for a considerable distance into the stroma. Thus, it is available for antibody binding regardless of fibril maturation and crosslinking. These data suggest that the II-5B2 epitope becomes unavailable when the telopeptide becomes crosslinked. By using these two monoclonal antibodies in serial sections, one can establish the crosslinking pattern of type II collagen in the tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminopropionitrile↗
PubMed1991

Joint toxic action of binary mixtures of osteolathyrogens at malformation-inducing concentrations for Xenopus embryos.

The joint action of binary mixtures of the osteolathyrogens semicarbazide (SC), beta-aminopropionitrile (beta APN) and penicillamine (PNC) were determined at malformation-inducing concentrations for Xenopus embryos. Tests were static with renewal every 24 h for the 96-h test period. Simultaneous tests on each individual component of the binary mixtures alone gave baseline malformation data (EC50) for joint action analyses. Toxic unit analysis and isobole diagrams were used to determine the type of joint action for 3:1, 1:1 and 1:3 mixtures of each combination. The joint action was concentration additive (strictly additive) for SC with beta APN and response additive (less-than-additive) for SC with PNC and beta APN with PNC. The joint actions were not changed when only osteolathyrogenic lesions, rather than all types of malformations, were considered. The different specific location and character of PNC lesions, as opposed to those for SC and beta APN, may signify a different type of osteolathyrogenic effect for PNC. The mixture testing approach has potential value in determining compounds that act similarly.

Abnormalities, Drug-Induced↗
PubMed1984

Development of topical BAPN delivery system for acute spinal cord injury in dogs.

Topical sustained release of various medications by a subdurally implantable device at the site of spinal cord injury is considered advantageous in the treatment of early symptoms of tissue damage. A typical case is the interference with collagenous scar by beta-aminopropionitrile, inhibiting collagen polymerization. Four materials, silicone, polyethylene, polytetrafluoroethylene (PTFE), and polyacrylonitrile-based hydrogel were evaluated for biocompatibility in subcutaneous implantations. The hydrogel, the least reactive, was then compared with silicone sheets as subcural implants. The histology favored the hydrogel as the most inert material, which was then used for the construction of soft, pliable pouches, releasing the drug through the hydrated wall at a rate controlled by an osmotic pump.

Aminopropionitrile↗
PubMed1993

Post-translational control of collagen fibrillogenesis in mineralizing cultures of chick osteoblasts.

Cultured osteoblasts from chick embryo calvaria were used as a model system to investigate the post-translational extracellular mechanisms controlling the macroassembly of collagen fibrils. The results of these studies demonstrated that cultured osteoblasts secreted a collagenous extracellular matrix that assembled and mineralized in a defined temporal and spatial sequence. The assembly of collagen occurred in a polarized fashion, such that successive orthogonal arrays of fibrils formed between successive cell layers proceeding from the culture surface toward the media. Mineralization followed in the same manner, being observed first in the deepest and oldest fibril layers. Collagen fibrillogenesis, the kinetics of cross-link formation, and collagen stability in the extracellular matrix of the cultures were examined over a 30 day culture period. Between days 8 and 12 in culture, collagen fibril diameters increased from < 30 nm to an average of 30-45 nm. Thereafter, diameters ranged in size from 20 to 200 nm. Quantitation of the collagen cross-linking residues, hydroxylysyl pyridinoline (HP) and lysyl pyridinoline (LP), showed that these mature cross-links increased from undetectable levels to concentrations found in normal chick bone. Analysis of the kinetics of their formation by pulse-chase labeling the cultures with [3H]lysine showed a doubling time of approximately 5 days. The relationships between cross-link formation, fibrillogenesis, and collagen stability were examined in cultures treated with beta-aminopropionitrile (beta-APN), a potent inhibitor of lysyl oxidase and cross-link formation. In beta-APN-treated cultures, total collagen synthesis was increased twofold, with no change in mRNA levels for type I collagen, whereas the amount of collagen accumulated in the cell layer was decreased by 50% and mineral deposition was reduced. The rate of collagen retention in the matrix was assessed by pulse-chase analysis of [3H]proline over a 16 day period in control and beta-APN-treated cultures. In control cultures, about 20% of the labeled collagen was lost from the cell layers over a 16 day period compared with > 80% in the presence of beta-APN. The beta-APN-treated cultures also showed a wider diversity of fibril diameters with a median in the > 45-60 nm range. In summary, these data suggest that cross-linking and assembly of collagen fibrils secreted by osteoblasts in vitro occur in a fashion similar to that found in vivo. The rate of cross-link formation is relatively constant and may be correlated with increasing collagen mass.(ABSTRACT TRUNCATED AT 400 WORDS)

Aminopropionitrile↗
PubMed1994

Effects of lathyritic drugs and lathyritic demineralized bone matrix on induced and sustained osteogenesis.

Demineralized bone matrix was implanted in normal and lathyritic rats. At 2 weeks, the bone that formed in the lathyritic animals had an elevated alkaline phosphatase activity and a reduced calcium content compared with the controls. Four weeks after implantation, these biochemical parameters were reversed, with a decrease in alkaline phosphatase activity and an increase in calcium content to control levels. The histology of the recovered implants revealed new bone formation. Lathyritic demineralized bone matrix was prepared from bones of rats fed beta-aminopropionitrile for 2 weeks (2-week BAPN-DBM) or 4 weeks (4-week BAPN-DBM), and was implanted in normal rats. Two weeks after implantation, both preparations of lathyritic demineralized bone matrix demonstrated early bone formation, although alkaline phosphatase activity and calcium content were reduced. By 4 weeks after implantation, no biochemical or histological evidence of bone formation remained at the site of the 4-week BAPN-DBM implants; continued but reduced bone formation was observed at the site of the 2-week BAPN-DBM implants. Reconstitution of inactivated normal demineralized bone matrix with the guanidine-soluble extracts restored the osteoinductive capacity. However, reconstitution of inactivated lathyritic demineralized bone matrix (4-week BAPN-DBM) failed to restore the osteoinductive capacity. These results indicate that the degree of crosslinking of the collagen matrix that acts as a carrier for osteoinductive proteins plays a key role in inducing and sustaining osteogenesis.

Aminopropionitrile↗
PubMed1994

Regulation of lysyl oxidase mRNA in dermal fibroblasts from normal donors and patients with inherited connective tissue disorders.

Lysyl oxidase (LO) is an extracellular copper-dependent enzyme that catalyzes the initial reaction in the formation of lysine or hydroxylysine-derived crosslinks during collagen biosynthesis. We have isolated a cDNA for human LO from skin fibroblast poly(A+)RNA by PCR using primers based on the recently published sequence of human LO. This cDNA probe detects a major mRNA of 4.2 kb on Northern blots of RNA from normal fibroblasts. The level of LO mRNA was not significantly affected by cell density or by ascorbate treatment. Treatment of skin fibroblasts with hydralazine (50 microM), which increases the mRNAs for both the alpha and the beta subunits of prolyl hydroxylase (PH) and the mRNAs for lysyl hydroxylase, also increased LO mRNA by fourfold over a 72-h time course. In contrast, hydralazine dramatically decreased the mRNAs for alpha 1(I) collagen. Administration of minoxidil (500 microM), which specifically decreases LH activity without affecting PH activity or collagen biosynthesis in skin fibroblasts, stimulated the level of LO mRNA. Neither the administration of penicillamine (100 microM), which interferes with collagen cross-linking, nor the administration of beta-aminopropionitrile, which is a strong irreversible inhibitor of LO, to fibroblasts significantly changed the levels of LO mRNA over a 72-h time course. However, bleomycin (0.6 microgram/ml) significantly decreased the 4.2-kb LO mRNA in contrast to the levels of the alpha 1(I) collagen mRNAs, which were unchanged. No significant change was observed in the steady-state levels of LO mRNAs in fibroblasts isolated from patients with certain connective tissue disorders, including Marfan syndrome, Menkes disease, cutis laxa, and pseudoxanthoma elasticum.

Aminopropionitrile↗
PubMed1994

Evidence that impaired intracellular collagen synthesis reduces proliferation in cultured rat hepatocytes.

Contribution of collagen to cell proliferation was studied in cultured hepatocytes. When alpha,alpha'-dipyridyl, an iron chelator which blocks hydroxylation of prolyl and lysyl residues of procollagen and expression of procollagen mRNA, was added to the medium of rat hepatocytes in primary culture, DNA synthesis of the cells was reduced in a dose-related manner without changes in protein synthesis. The reduction of collagen synthesis was parallel with the changes of DNA synthesis. The addition of P-1894B or minoxidil, which inhibits specifically prolyl hydroxylase or lysyl hydroxylase, respectively, also produced similar results. However, the DNA synthesis was not affected by beta-aminopropionitrile fumarate, which inhibits cross linking in extracellular collagen maturation, nor by purified bacterial collagenase. Intracellular processing of collagen synthesis may be required for proliferation in cultured rat hepatocytes.

2,2'-Dipyridyl↗
PubMed2001

Characterization of a model compound for the lysine tyrosylquinone cofactor of lysyl oxidase.

We characterized a model compound for the lysine tyrosylquinone (LTQ) cofactor of lysyl oxidase which is one of the mammalian copper-dependent amine oxidases. The model compound, 4-butylamino-5-methyl-o-quinone, was prepared from n-butylamine and 4-methylcatechol by the oxidation with sodium iodate and characterized by spectroscopic analyses. The absorption maximum at 494 nm is consistent with that of lysyl oxidase. The model compound was capable of deaminating benzylamine to benzaldehyde at 37 degrees C in buffered aqueous acetonitrile. The aldehyde production was markedly elevated in the presence of the Cu(II)-EDTA complex but inhibited by free Cu(II). The catalytic cycle was observed at pH 10 in the presence of Cu(II), and the pH activity profile showed a broad optimum at about pH 9.0. In the presence of beta-aminopropionitrile and upon deoxygenation with N2 aldelyde, production was decreased. The important features of the reaction were consistent with the enzymatic reaction.

Acetonitriles↗
PubMed1997

Synthesis of collagen by bovine chondrocytes cultured in alginate; posttranslational modifications and cell-matrix interaction.

The extracellular matrix synthesized by articular chondrocytes cultured in alginate beads was investigated. Collagen levels increased sigmoidally with time and remained constant after 2 weeks of culture. The presence of cartilage-specific type II collagen was confirmed immunohistochemically. Predominantly type II collagen was present in the alginate bead, as reflected by the unique extent of lysyl hydroxylation, glycosylation, and pyridinoline crosslink formation measured. Collagen crosslinks, predominantly hydroxylysylpyridinoline (> 93%), were observed after 7 to 11 days of culture and their formation was effectively blocked by beta-aminopropionitrile (BAPN). Unexpectedly, BAPN treatment resulted in a 100% increase of collagen levels, without influencing cell proliferation and proteoglycan levels. In control cultures 90% of the synthesized collagen was retained in the cell-associated matrix, while in BAPN-treated cultures half of the collagen was found in the interterritorial matrix compartment further removed from the cells. This suggests that impaired crosslinking of collagen interferes with pericellular collagen deposition, causing upregulation of collagen synthesis by impaired cell-matrix interactions. Integrins are likely to be involved in this feedback inhibition by extracellular collagen since the cyclic RGD-containing peptide CGRGDSPC downregulated collagen synthesis by 37%.

Alginates↗
PubMed1999

Abnormal collagen assembly, though normal phenotype, in alginate bead cultures of chick embryo chondrocytes.

The collagens produced by chick embryo chondrocytes cultured in alginate beads were investigated both biochemically and ultrastructurally. The cartilage phenotype is maintained for at least 14 days, as indicated by the production of the cartilage-specific collagens II, IX, and XI and the absence of collagen I. There were differences in the distributions of collagens among the three different compartments analyzed (cells and their associated matrix, further-removed matrix (released by alginate solubilization), and culture medium), with large amounts of collagen IX (mainly in proteoglycan form) in the culture medium. Inhibition of lysyl oxidase activity by beta-aminopropionitrile led to an overall decrease in collagen production. In contrast to the biochemical observations, collagen ultrastructure in the extracellular matrix of alginate cultures was not in the form of the expected 64-nm banded fibrils, but rather in the form of segment-long-spacing-like crystallites. This abnormal structure is likely to be a result of alginate disrupting normal assembly. We conclude that, in this system, the native fibrillar structure of the collagenous matrix is not essential for the maintenance of the differentiated phenotype of chondrocytes.

Alginates↗
PubMed1994

Semicarbazide-sensitive amine oxidases in sheep plasma: interactions with some substrates and inhibitors.

The present study has examined the affinities of sheep plasma semicarbazide-sensitive amine oxidase (SSAO) enzymes for a range of aliphatic amines and also the effects of two inhibitory compounds, beta-aminopropionitrile (BAPN) and mexiletine. Two kinetically separable enzyme activities appeared to be responsible for the metabolism of amines containing 2-5 carbon atoms while the deamination of higher amines and methylamine and allylamine produced kinetic plots characteristic of only one enzyme activity. When benzylamine metabolism was used as an indication of enzyme activity, the two inhibitors had different effects. BAPN exhibited predominantly a mixed pattern of inhibition while the effects of low concentrations of mexiletine were largely competitive. These results present evidence confirming the presence of two kinetically separable SSAO activities in sheep plasma, although we must await the development of highly selective inhibitors before these two activities can be fully resolved.

Amine Oxidase (Copper-Containing)↗
PubMed1980

Long term lathyrism and atherogenic diet in the rat. Protective action of pyridinol carbamate.

In the rat, prolonged administration (7 months) of Beta-Aminopropionitrile in association with a hyperlipidic diet caused the formation of widespread pronounced atheroma. The addition of Pyridinol Carbamate during the treatment minimized and retarded the appearance of lipid overload lesions. The histological modifications were found together with an increase in the free cholesterol fraction. These two observations explain the protective role of Pyridinol Carbamate on the wall of the aorta.

Aminopropionitrile↗
PubMed1991

Local effects of impaired mechanical properties of collagen on bone formation and resorption.

To study the relationship between the mechanical properties of collagen and the bone turnover, 2-week-old Balb/C mice were fed on a diet containing 0.25% Beta aminopropionitrile (B-APN), a potent inhibitor of collagen crosslink formation, for 3 weeks. Mandibular incisor socket was selected for the analysis of bone formation and resorption parameters. Plastic embedded sections stained with toluidine blue and cut at 4 microns were used to analyze the average area of bone lamellae, bone-forming surface, and the number of osteoblasts/mm of forming surface. Similar sections were used to localize acid phosphatase on resorbing surfaces and within the osteoclasts, while bone alkaline phosphatase was determined by a colorimetric method. Morphometric analyses showed that the area of newly formed bone lamellae, total forming surface, number of osteoblasts and the Alk. Pase activity were significantly lower in B-APN-fed mice as compared to the controls. There was a concomitant smaller, but significant, reduction in total resorption surface, active resorption surface and the number of osteoclasts. These results suggest that the regulation of bone formation and resorption at this site, which is independent of systemic regulation, is influenced by the mechanical properties of the collagenous matrix, which in turn may have a significant effect on the existing pool of bone-forming cells, but may not influence the recruitment of new cells.

Acid Phosphatase↗
PubMed1985

Histamine and collagen levels in the lathyritic chick embryos after administration of 48/80.

The studies were undertaken to investigate the influence of compound 48/80 on histamine (Hi) and collagen levels of chick embryos after administration of lathyrogen factor, beta-aminopropionitrile (BAPN). Hi and soluble collagen levels in bones (tibia and femur) and skin were significantly higher in the embryos treated with BAPN. Compound 48/80 administered together with BAPN lowered Hi and soluble collagen in the bones and skin as compared with the embryos treated with BAPN alone. Both, in the skin and bones, 48/80 was found to be a protective factor against the changes in biosynthesis of collagen.

Aminopropionitrile↗
PubMed2001

Force deficits after stretches of activated rat muscle-tendon complex with reduced collagen cross-linking.

The forces produced during stretches of passive and activated muscles, and isometric force deficits after stretching of activated muscles were examined in rat plantor flexor muscle-tendon complexes with reduced collagen cross-links (pyridinoline). Female Sprague-Dawley rats (n = 6, age 87 days) were injected twice daily for 43 days with beta-aminopropionitrile (BAPN, 333 mg/kg/day i.p.), an inhibitor of lysyl oxidase, which is responsible for the production of collagen cross-links. The relative weights of the plantar flexor muscles were similar for BAPN and saline-injected (control, C) rats (n = 6). Pyridinoline was lower in the tendon (22.9%), and in the plantaris (17.1%), and soleus (7.4%) muscles (P < 0.05), with no changes observed in collagen content (hydroxyproline), as determined by high-pressure liquid chromatography. At an ankle position of 90 degrees, groups had similar forces at 5, 10, 20, 40, 60 and 80 Hz before stretching. Forces at 40 degrees with stretches of the passive muscles (five times from 90 degrees to 40 degrees) were lower for all stretches in BAPN-injected rats (P < 0.05). Isometric force deficits resulting from stretches of activated muscles (80 Hz, 20 times from 90 degrees to 40 degrees, rest intervals 3 min) followed similar courses for BAPN-injected and C rats, and were 51.1 (2.4)% (C) and 54.7 (4.6)% (BAPN) before the last stretch. After 1 h of rest, isometric force deficits were 26% and 29% larger at 10 Hz and 5 Hz, respectively, in BAPN-treated rats (P < 0.05). The reduction in BAPN-injected collagen cross-linking of the skeletal muscle-tendon complex reduced the forces produced during stretches without muscle stimulation (i.e. passive stretch), and stretching of activated muscles produced larger isometric force deficits only at low stimulation frequencies.

Achilles Tendon↗
PubMed1979

Effect of metabolic alteration of periodontal fibers on orthodontic tooth movement. An experimental study.

In the present study orthodontic force was applied to the molars of rats treated with the lathyrogen beta-aminopropionitrile (BAPN). New bone formation was measured at two alveolar locations after 9 days of force application. Observation resulted in the following conclusions: 1. New alveolar bone formation in response to orthodontic force in BAPN-treated rats statistically exceeded corresponding bone formation in control animals when measured at two tension sites in the periodontal ligament. 2. BAPN administration produced disorganization of the collagenous fibers of the periodontium of experimental animals. Multiple eosinophilic cell-free areas were found distributed throughout the radicular portions of affected periodontal ligaments. Normal ligament function architecture was disrupted in treated animals. The areas of periodontium surrounding orthodontically treated teeth exhibited relatively normal organization under these conditions, while the periodontium of adjacent nonorthodontically treated teeth was markedly disorganized. Orthodontic stimulation of the periodontium of BAPN-treated rats may have disrupted the formation of eosinophilic cell-free areas characteristically seen in the periodontium of the experimental group. 3. The present results suggest that the typical histologic response to orthodontic force application can occur in the presence of a chemically and physically altered periodontium. The quantitative data collected infer that fiber tension on the alveolus may not be absolutely necessary to stimulate bone formation. Distortion of the alveolus related to force application may be a more important factor initiating bone response. However, the fibers of the periodontium may play a passive role in transferring orthodontic force to the alveolus.

Alveolar Process↗
PubMed1990

An ultrafiltration assay for lysyl oxidase.

A modification of the original microdistillation assay for lysyl oxidase is described in which Amicon C-10 microconcentrators are used to separate, by ultrafiltration, the 3H-labeled products released from a [4,5-3H]-lysine-labeled elastin substrate. Enzyme activity is determined by scintillation counting of the ultrafiltrate, after subtraction of radioactivity released in the presence of beta-aminopropionitrile, a specific inhibitor of the enzyme. Conditions are described which optimize both the sensitivity and the efficient use of substrate. The assay shows linear inhibition of activity in up to 1 M urea; hence, as the enzyme is normally diluted in the assay, samples in 6 M urea can be assayed directly, without prior dialysis, and corrected for partial inhibition. Comparable results are obtained when enzyme activity is assayed by ultrafiltration or microdistillation. The assay is simple and convenient and, by using disposable containers throughout, it eliminates the need for time-consuming decontamination of radioactive glassware.

Amino Acid Oxidoreductases↗
PubMed1983

Evaluation of (+)-catechin action on lysyl oxidase activity in aortic tissue.

Small amounts of (+)-catechin (5 mg/kg body wt) administered intramuscularly to 8-day-old chicks raised the lysyl oxidase activity in aorta about 20%. (+)-Catechin had no effect on chicks that were copper-deficient. In the deficient chicks, (+)-catechin treatment prompted a substantially stronger increase in lysyl oxidase activity in response to CuSO4. The observed increments in lysyl oxidase activity in vivo were sensitive to inhibition by beta-aminopropionitrile (BAPN), suggesting that (+)-catechin was affecting the enzyme. (+)-Catechin in the assay medium partially inhibited lysyl oxidase activity. With excess copper ions present, (+)-catechin catalyzed a very strong release of volatile tritium from the substrate proteins. The release of tritium, indicative of lysyl oxidase activity, was not blocked by BAPN, suggesting that the activity in vitro was not enzyme catalyzed.

Amino Acid Oxidoreductases↗