Biomedical subjects

F Hui

Publications and source records attributed to F Hui.

At least 37 records · Page 2Linked to original sources

PubMed1997

Agents that block fibronectin fragment-mediated cartilage damage also promote repair.

OBJECTIVE AND DESIGN: The objective was to determine if agents that suppress catabolism might also enhance repair of irreversibly damaged cartilage. MATERIAL: Articular cartilage from bovine metacarpophalangeal joints was studied in explant culture. TREATMENT: Fibronectin fragments or IL-1 alpha, which potently cause proteoglycan (PG) loss from cartilage, were added to cultures also containing the catabolism-blocking agents: insulin-like growth factor-1, or N-acetylcysteine, or Arg-Gly-Asp-Ser peptide, and the effects of these agents on blocking PG loss determined. To test for repair or restoration of PG, cartilage was first damaged, damage agents removed and inhibitory agents added. METHODS: Each mean and SD value for cartilage PG content was determined by assays of papain digests of cartilage from three similar cultures. RESULTS: The agents either partially or fully blocked PG loss and promoted repair. CONCLUSIONS: Normally irreversible cartilage damage was reversed by slowing ongoing catabolic processes during attempted repair. Thus, catabolic inhibitors have reparative potential.

Acetylcysteine↗

PubMed1997

Hyaluronic acid suppresses fibronectin fragment mediated cartilage chondrolysis: II. In vivo.

Intra-articular sodium hyaluronic acid (HA) has been used as a treatment intervention in the management of osteoarthritis. It has been observed that HA can coat the articular surface, and thus, has been suggested to provide a possible prophylactic barrier for the articular cartilage. In an accompanying manuscript (Homandberg et al.), we report that a commercially available high-molecular-weight HA (approximately 800-kDa, ARTZ, Seikagaku Corp.) can partially block fibronectin fragment (Fn-f)-mediated cartilage injury in vitro. Herein we report a study of the effects of intra-articular HA on an in vivo animal model of Fn-f-mediated cartilage injury. Rabbit knees were injected with Fn-f, and after 1 week, the cartilage proteoglycan (PG) content had decreased to 59 +/- 8% of control. In sharp contrast, PG content in knees receiving pre-treatment with HA followed by Fn-f injection had only decreased to 85 +/- 27% of control (P < 0.01). Similarly, the PG content in knees receiving an injection of Fn-f, followed by an injection of HA were significantly higher (74 +/- 18% of control) than Fn-f injured knees with no treatment (P < 0.02). Intra-articular HA alone had no effect on cartilage PG content. The results in this study suggest that HA is effective in partially preventing Fn-f mediated cartilage injury, most likely by coating the articular surface. Further, HA treatment after Fn-f injury may facilitate restoration of matrix components.

Animals↗

PubMed1997

Hyaluronic acid suppresses fibronectin fragment mediated cartilage chondrolysis: I. In vitro.

A commercial preparation of 800-kDa hyaluronic acid (HA), (ARTZ from Seikagaku, Inc.), has been used as a therapeutic intervention in the treatment of osteoarthritis (OA). We tested the effect of this HA form, HA/800, in an in vitro cartilage chondrolytic system in which a specific amino-terminal 29-kDa fragment of fibronectin (Fn-f) penetrates cartilage tissue to activate chondrocytes to amplify two major chondrolytic activities: suppression of proteoglycan (PG) synthesis and induction of matrix metalloproteinases. We report that HA/800 did not block damage by Fn-f in serum free cartilage cultures. However, HA/800 was effective in blocking the ability of 100 nM Fn-f to cause the degradation and release of half of the total cartilage PG from cartilage in 10% serum/DMEM cultures. While the Fn-f caused a half-time for PG release of 3 days, continuous exposure to 0.1 or 1 mg/ml HA/800 slowed the half-time to 12 days. Further, a single 1 day pre-incubation with 0.1 or 1 mg/ml HA/800 was sufficient to decrease the half-time of 100 nM Fn-f mediated PG depletion to 7 and 12 days, respectively. HA/800 completely blocked the effect of 10 nM Fn-f. Blocking of Fn-f-mediated cartilage PG depletion was associated with a decreased concentration of Fn-f on the superficial cartilage surface and decreased penetration into the cultured cartilage tissue. Further, the two major chondrolytic activities of the Fn-f, suppression of synthesis of PG and enhanced release of stromelysin-1, were suppressed by HA/800. HA/800 also partially restored PG in cartilage first damaged with the Fn-F. We conclude that HA/800 slows Fn-f-mediated cartilage chondrolysis in vitro and has some reparative potential. The damage blocking activity appears to be associated with the ability of HA/800 to block penetration of the Fn-f, rather than with direct effects on cartilage tissue.

Animals↗

PubMed1997

Hippocampus. Normal magnetic resonance imaging anatomy with volumetric studies.

MR imaging sections of the hippocampus in different orthogonal planes are illustrated. Matching coronal slices in T2-weighted and gradient echo sequences allow a comparative evaluation of the intricate structure of the hippocampus and its relationship with adjacent structures. Techniques in volumetric assessment of the hippocampus are discussed in light of recent advancement in MR imaging.

Hippocampus↗

PubMed1997

Surgical excision of intracranial arteriovenous malformations after preoperative embolisation with N-butylcyanoacrylate.

The aim of this study was to determine the usefulness of preoperative embolisation of intracranial arteriovenous malformations (AVMs) with N-Butylcyanoacrylate (NBCA) since the introduction of this interventional neuroradiology technique in March 1994 at Tan Tock Seng Hospital, Singapore. Twenty-one patients who underwent complete surgical excision of their AVMs (proven on postoperative angiograms) were studied. Eight patients had preoperative embolisation with NBCA prior to surgical excision of their AVMs. Thirteen patients had excision of their AVMs without preoperative embolisation and these were used as the control group. The parameters studied were the patient's AVM characteristics, the amount of blood loss and the length of operative time. Statistically significant reduction in blood loss occurred in Spetzler and Martin Grade 3 and 4 AVMs but not in Grade 1 and 2 AVMs undergoing preoperative embolisation with NBCA. Operative time was reduced in Grade 3 and 4 AVMs but not in Grade 1 and 2 AVMs, although this was not statistically significant. Preoperative embolisation of AVMs is hence a useful and important adjunct in the management of patients with Grade 3 and 4 AVMs of the brain undergoing conventional open microneurosurgery.

Adolescent↗

PubMed1996

Fibronectin fragment mediated cartilage chondrolysis. II. Reparative effects of anti-oxidants.

In an accompanying manuscript, it was shown that the cartilage chondrolytic activities of fibronectin fragments (Fn-f), which are mediated through catabolic cytokines such as TNF-alpha, IL-1 and IL-6, could be suppressed by anti-oxidants (AOs). The AOs neutralized reactive oxygen species (ROS) which are known to mediate catabolic cytokine action. The objective in this work was to test whether AOs would promote restoration of proteoglycan (PG) in Fn-f treated cartilage, since under normal culturing conditions, PG is not restored after removal of the Fn-f. Cartilage was first cultured with an amino-terminal 29-kDa Fn-f to cause loss of about half of the total PG and then treated with NAC (1 and 10 mM) or glutathione (10 microM) or DMSO (0.1 or 1%). Treatment with NAC and glutathione maximally caused restoration of PG within 14 days to normal or supernormal levels, while DMSO was less effective. Catalase, but not superoxide dismutase, enhanced PG content to a small but significant extent. The restoration of PG in Fn-f treated cartilage occurred throughout the full depth of the cartilage slices as shown by histochemical analysis. However, removal of the AO allowed a subsequent decrease in PG content suggesting that the AOs had not blocked cytokine expression but had merely suppressed cytokine activities. Addition of NAC to IL-1 treated cartilage promoted a restoration of PG, while addition to chymopapain or trypsin treated cartilage was not very effective, suggesting that the effect of AOs requires a cytokine driven damage system. We conclude that the AOs promote a restoration of PG in the Fn-f treated cartilage by suppressing the effects of catabolic cytokines. The data suggest a potential for AOs in reversing tissue damage caused by cytokines.

Acetylcysteine↗

PubMed1996

Fibronectin fragment mediated cartilage chondrolysis. I. Suppression by anti-oxidants.

Fibronectin fragments damage cartilage in vitro by greatly enhancing metalloproteinases and suppressing proteoglycan (PG) synthesis which results in severe cartilage PG depletion. Since reactive oxygen species (ROS) have been implicated in catabolic cytokine action and preliminary data suggested that catabolic cytokines such as TNF-alpha, IL-1 alpha, IL-1 beta and IL-6 are responsible for fibronectin fragment mediated damage, selected anti-oxidants (AOs) were tested as inhibitors of cytokine. ROS and fibronectin fragment activity. Damage was measured by depletion of cartilage PG during tissue culture. The AO, N-acetylcysteine (NAC), decreased the extent of cartilage PG depletion caused by TNF-alpha and IL-1 alpha and by the ROS, hydrogen peroxide and superoxide anion, confirming that the cytokines operate through ROS and that ROS can initiate cartilage PG depletion. NAC at 0.1 and 1 mM, totally suppressed PG depletion caused by a highly potent amino-terminal 29-kDa fibronectin fragment (Fn-f) for 14 days in culture. NAC at 10 mM totally blocked Fn-f mediated PG depletion for 21 days and increased the cartilage PG content by 30% above normal levels. Glutathione (10 microM) and DMSO (1%) were also totally effective while catalase and superoxide decreased Fn-f mediated damage only during the first week and superoxide dismutase alone caused damage after 1 wk. The AOs caused protection by reducing the major catabolic activities of the Fn-f: enhanced release of stromelysin-1 (MMP-3) and suppression of PG and protein synthesis. NAC also decreased normal rates of PG degradation and increased the half-lives of labeled PG in both control and Fn-f treated cartilage. We conclude that the Fn-f mediates cartilage chondrolysis through ROS, consistent with the involvement of catabolic cytokines in the Fn-f mechanism, and that AOs greatly reduce Fn-f mediated cartilage chondrolysis. In an accompanying manuscript we also report that AOs promote reparative responses in Fn-f and cytokine treated cartilage.

Allopurinol↗

PubMed1996

Association of proteoglycan degradation with catabolic cytokine and stromelysin release from cartilage cultured with fibronectin fragments.

Addition of fibronectin fragments to bovine articular cartilage explant cultures results in enhanced release of metalloproteinases and rapid cartilage proteoglycan (PG) degradation and loss. The chondrolysis begins with rapid PG degradation which markedly slows after 1 week. Preliminary observations suggest that catabolic cytokines mediate chondrolytic activities of the fibronectin fragments. The objectives of this work were to investigate the correlations between: (a) release of specific cytokines; (b) release of the metalloproteinase (MMP), stromelysin-1 (MMP-3); (c) release of the tissue inhibitor of MMPs, TIMP-1, and; (d) degradation and release of PG from cultured cartilage. We report that human articular cartilage cultured with an amino-terminal 29-kDa fragment (Fn-f) at 0.1 microM, released enhanced levels of TNF-alpha, IL-1beta, and IL-1alpha with peaks at Days 2, 3, and 9, respectively. MMP-3 release was elevated with a peak at Day 6 and a profile similar to that for the Fn-f-induced cartilage PG depletion. IL-6 release was enhanced within 2 days and continued at the same level throughout the culture period but this did not lead to enhanced release of TIMP-1, a known activity of IL-6. These data suggest that in the early chondrolytic events induced in cultured cartilage by Fn-f, enhanced MMP-3 release and maximal degradation and release of PG from cultured cartilage are kinetically associated with elevated release of the catabolic cytokines, TNF-alpha, IL-1beta, and IL-1alpha. Further, a later period of slowing PG loss and slowing MMP-3 release is associated with greatly slowed release of these cytokines, but prolonged release of IL-6. This model of cartilage damage may be useful for studies of the interplay between cytokines and the effects of combinations of cytokines on cartilage homeostasis.

Aged↗

PubMed1995

Cerebral arteriovenous malformations in children. Management of 179 consecutive cases and review of the literature.

Over the past 10 years (1982-1992), we have been actively involved in the management of 179 cerebral arteriovenous malformations (CAVMs) in children and infants. Seventy-seven were true vein of Galen malformations (VGAMs) and 102 were pial AVMs (PAVMs), i.e., developed in the subpial space. Hemorrhage occurred as the first symptom in 50% of the children with pial AVMs, but was present in none of the VGAM cases. Only 31 children were found to be unsuitable for endovascular treatment, and in 124 cases embolization was indicated as the primary treatment (104 embolization performed). Only 21 children underwent a direct surgical approach (none in the VGAM group). In the embolized group in whom treatment has been completed (n = 56), 8 children died, 39 have an anatomical cure, and 34 are clinically normal. In the group under treatment (n = 48), 16 are not normal. The problems are timing and the aims (total or partial treatment) of the therapeutic procedures. In the nonembolized group (n = 31), 8/13 of the pial lesions were operated on (no mortality, 2 patients with moderate neurological deficits). In the VGAM group 13/18 died and 4 had spontaneous thrombosis (only 1 is neurologically normal). In the nonembolized group 13 lesions have been completely excluded, but only 5 patients are neurologically normal. This fact again stresses the need for prognostic evaluation before treatment and a clear definition of the treatment aims. Analysis of a large number of published series on the management of children with AVMs (1017 cases) reveals inconsistencies that hamper proper evaluation and comparison. In our experience, endovascular treatment always seems to be the best primary treatment in both VGAMs and PAVMs. However, management of children with these lesions requires a large multidisciplinary team, which is the only way of offering the most suitable and effective treatment, the sole guarantee of a good result.

Adolescent↗

PubMed1995

Genotypic and phenotypic characterization of HIV-1 isolated from patients receiving (--)-2',3'-dideoxy-3'-thiacytidine.

We attempted to determine whether HIV-1 developed resistance to (--)-2',3'-dideoxy-3'-thiacytidine ((--)-3TC or 3TC, lamivudine) in patients with advanced human immunodeficiency virus type 1 (HIV-1) infection during therapy with 3TC. Genotypic analysis of HIV-1 strains isolated from 6 patients receiving 3TC revealed that as early as 2 months of therapy, HIV-1 developed a Met to Val amino acid substitution at codon 184 (Met184-->Val) in the reverse transcriptase-coding region of the pol gene. A detailed study of a series of HIV-1 strains isolated from a patient demonstrated that Met at codon 184 was first substituted with Ile by 2 weeks of 3TC therapy, followed by the substitution with Val by 8 weeks. All HIV-1 strains with the Met184-->Val substitution were profoundly less susceptible to 3TC (1800- to 5500-fold decreased sensitivity) as compared to pretherapy virus strains. These strains were also moderately less sensitive to 2',3'-dideoxycytidine (4.5- to 9-fold), but more sensitive to 3'-azido-2',3'-dideoxythymidine (2- to 14-fold). A decrease in viremia levels and an increase in CD4 counts were observed early in therapy; however, these changes were only transient. Our data suggest that reversal of such beneficial changes is associated with the Met184-->Val substitution of the pol gene of HIV-1. The data also suggest that 3TC, as a single agent, may induce virologic and immunologic improvement in patients with advanced HIV-1 infection, but only transiently.

Adult↗

PubMed1995

Mesial temporal lobe epilepsy in Singapore.

Mesial temporal lobe epilepsy due to mesial temporal sclerosis is a distinctive syndrome and a surgically remediable form of epilepsy. We present 26 Singaporean cases of mesial temporal lobe epilepsy defined by clinical, electroencephalographic and MR features and validated by good surgical outcome (12 seizure free, 5 with two or fewer seizures) in all 17 patients who have so far undergone surgery and who have been followed up for at least 6 months. Sixty-five percent of patients experienced their first seizure in the setting of a febrile illness. Seventy-three percent of patients had seizure onset before the age of 10 years and the median interval between seizure onset and intractability of seizures was 3.75 years. 80.7% of patients had an aura and an equal number had at least one lateralizing sign during their seizures. Sixty-four percent of patients had predominantly unilateral anterior temporal interictal spikes. Eighty-eight percent of patients had seizures which were lateralised on scalp ictal EEG. MRI abnormalities were most frequently seen in the head and body of the hippocampal formation. Asymmetric hippocampal atrophy was more common than hippocampal T2 or T2* signal changes. There is much similarity in characteristics of mesial temporal lobe epilepsy in our population compared to what has been published regarding Caucasian subjects.

Adolescent↗

PubMed1995

Neuronal migration disorder presenting with epilepsy: a report of five illustrative cases.

Neuronal migration disorders are an uncommon but well-recognised cause of medically intractable epilepsy. The increasing availability of magnetic resonance imaging of the brain has made it possible to diagnose this condition ante-mortem. There are several types of migration disorders, each with different radiological and clinical features. A case each of focal cortical dysplasia, focal subcortical heterotopia, double cortex syndrome, periventricular nodular heterotopia and closed lip schizencephaly is presented to highlight the distinctive features of each entity.

Adult↗

PubMed1994

Arg-Gly-Asp-Ser peptide analogs suppress cartilage chondrolytic activities of integrin-binding and nonbinding fibronectin fragments.

We have reported that Fn fragments (Fn-f), which have been detected in synovial fluids of osteoarthritis and rheumatoid arthritis patients, can potently cause cartilage chondrolysis and depress proteoglycan (PG) synthesis in cartilage tissue cultured as explants. Amino-terminal 29-kDa, gelatin-binding 50-kDa, and integrin-binding 140-kDa Fn-f are active. In order to investigate the mode of action and devise means of blocking the damage mediated by all Fn-f, we have tested the effects of various analogs resembling the integrin binding sequence, Arg-Gly-Asp-Ser, on blocking Fn-f-mediated chondrolysis. The analog peptides, Gly-Arg-Ala-Asp-Ser-Pro-Lys and Arg-Phe-Asp-Ser, at concentrations as low as 1 microM, blocked the effects of all three Fn-f on cartilage degradation, while the native sequence peptide, Arg-Gly-Asp-Ser, had very low Fn-f-blocking activity and by itself caused cartilage damage. Random sequence peptides dissimilar to the analog sequences were inactive as inhibitors as well as was a sequence analog, Phe-Asp-Arg-Ser, related to the Arg-Phe-Asp-Ser inhibitor. The analog inhibitory peptides decreased rates of Fn-f-mediated PG degradation and release from cartilage and decreased Fn-f-mediated PG synthesis depression. The analog inhibitory peptides alone had no detectable effect on cartilage PG degradation or PG synthesis rates. These data show that the chondrolytic activities of integrin-binding and nonbinding Fn-f can be blocked by synthetic peptide analogs of the Arg-Gly-Asp-Ser sequence and suggest that these peptides may be useful for blocking other activities of Fn-f.

Amino Acid Sequence↗

PubMed1994

Cartilage chondrolysis by fibronectin fragments is associated with release of several proteinases: stromelysin plays a major role in chondrolysis.

We have reported that three different Fn fragments (Fn-f) added to bovine articular cartilage cultured in serum-free DMEM cause marked elevation of proteoglycan (PG) degradation and release into the culture media. We report here that the PG release required the continual presence of Fn-f, that PG release still occurred when serum-free cultures were switched to bovine synovial fluid media, and that addition of recombinant IGF-1, TGF-beta, and recombinant interferon gamma to cultures did not affect Fn-f-mediated PG release. The Fn-f caused a 25-fold enhanced release of stromelysin-1 protein from cartilage by Day 1 and up to 120-fold by Day 3. The stromelysin form released was 43 kDa, the activated form of pro-stromelysin-1. This stromelysin form apparently played a major role in Fn-f-mediated PG release, since addition of Sepharose-bound anti-stromelysin-1 to cartilage cultures greatly slowed rates of PG release. Potential activators of pro-stromelysin-1, plasmin, and u-PA (urinary plasminogen activator), were also detected in conditioned media of Fn-f-treated cartilage. u-PA levels were increased in the presence of the Fn-f but by only a few fold. Addition of alpha-1-antiproteinase inhibitor, which can block enzymatic activity of u-PA, was found to inhibit about half the PG-releasing activity of the Fn-f. Levels of TIMP-1, the 30-kDa tissue inhibitor of metalloproteinases, which can inhibit stromelysin, doubled within 24 h when a Fn-f was added to culture. These data suggest that stromelysin-1 may be a major mediator of Fn-f-mediated PG release from cartilage.

Animals↗

PubMed1994

High concentrations of fibronectin fragments cause short-term catabolic effects in cartilage tissue while lower concentrations cause continuous anabolic effects.

We reported earlier that Fn fragments (Fn-f) added to bovine articular cartilage cultured in serum-free DMEM cause marked elevated release of protease activity within a few days. This results in greatly elevated rates of release of proteoglycan (PG). We have now extended our studies to 4-week cultures of cartilage in the presence of 10% serum. We report here that cartilage cultured with 0.01, 0.1, and 1 microM of an amino terminal 29-kDa Fn-f in 10% serum accelerated the loss of PG from the tissue during the first few days in a concentration-dependent manner. However, beyond this period PG content decreased much more slowly. During this early period, the 29-kDa Fn-f decreased rates of protein and PG synthesis up to 50% in a concentration-dependent fashion. Beyond this period, the synthesis rates began to increase in a mode inversely related to 29-kDa Fn-f concentration, up to 135% of Fn-f free control values. However, during the entire culture period, cartilage cultured with 1 nM 29-kDa Fn-f had higher PG contents and had enhanced rates of protein and PG synthesis. Since 1 nM 29-kDa Fn-f stabilized cartilage against decreases in PG content, we tested its ability to block the activity of higher 29-kDa Fn-f concentrations. Cartilage was preincubated for 7 days with 1 nM 29-kDa Fn-f, and then the culture adjusted to 100 nM 29-kDa Fn-f to cause PG depletion. The preincubated cartilage showed markedly enhanced resistance to PG depletion. Since the protective effect was similar to known properties of IGF-1, the ability of 20 ng/ml IGF-1 to block against the effects of 100 nM Fn-f was tested and shown to be similar in magnitude to that of 1 nM 29-kDa Fn-f. We propose that the initial catabolic effects of higher concentrations of Fn-f, followed by the later anabolic effects, may aid in tissue repair. Also, the continuous anabolic effects of lower concentrations may be involved in tissue homeostasis.

Amino Acid Sequence↗

PubMed1994

Prognosis of antenatally diagnosed vein of Galen aneurysmal malformations.

In our experience of 168 consecutive cerebral arteriovenous shunts, all antenatally diagnosed lesions were vein of Galen aneurysmal malformations (VGAMs). This series consists of 18 cases of VGAMs detected by ultrasound during the third trimester of pregnancy. There were 12 normal vaginal deliveries, 5 deliveries by cesarean section, and 1 induced abortion. Sixteen newborns (94%) presented with systemic cardiac manifestations as the first clinical symptoms; 12/16 were managed effectively by digitalo-diuretic treatment, while 4 (25%) died shortly after birth from acute heart and/or multiorgan failure with extensive brain damage. Twelve babies underwent embolization via the arterial route in infancy (2 at 2 months of age). Total exclusion was obtained in 8 babies (67%, 3 with 6 months follow-up). Furthermore, 67% of the newborns managed by our team are neurologically normal (Denver and Brunet-Leizine tests). These results emphasize that the pessimism that follows antenatal discovery of these lesions and the previous assumption of a bad prognosis for VGAMs can nowadays be reviewed in the light of transarterial endovascular therapy applied according to a strict clinicoradiological protocol. Interventions in the neonatal period are rarely required. Generally, poorly timed mechanical therapy should be discouraged.

Algorithms↗

PubMed1994

Paraspinal arteriovenous shunts in children.

Arteriovenous shunts within the spinal canal and in the paraspinal region are unusual. Spinal cord and dural arteriovenous communications have been the subject of numerous reports but paraspinal shunts causing venous congestion in the spinal canal are rarer and may present special problems in diagnosis and management. We describe three children with paraspinal arteriovenous malformations, associated with overt or potential venous congestion in the spinal canal. In each case, the lesion was successfully obliterated by endovascular therapy. Embolisation with permanent occlusive agents is an effective treatment for these rare but potentially debilitating lesions.

Arteriovenous Malformations↗

PubMed1993

Fibronectin fragments alter matrix protein synthesis in cartilage tissue cultured in vitro.

We reported earlier that fibronectin fragments (Fn-f) added to bovine articular cartilage cultured in serum-free culture causes marked protease expression with resultant proteoglycan (PG) degradation and release into the culture media. We have further characterized the effects of Fn-f by studies of the effects on proteoglycan, collagen, general protein, and DNA synthesis and reversibility of the cartilage damage. We report here that the most active Fn-f, a 29-kDa amino-terminal Fn-f, when added to a 1 microM concentration, depressed PG and general protein synthesis in cartilage by over 50% within 24 h, as measured by sulfate and methionine/cysteine incorporation, respectively. This same Fn-f decreased PG synthesis throughout the full thickness cartilage section as shown by autoradiography. PG and general protein synthesis were significantly depressed within 24 h by 29-kDa Fn-f concentrations as low as 10 nM. Synthesis rates were effected by 100-fold lower Fn-f concentrations than was induction of proteinases. Removal of the 29-kDa Fn-f allowed a gain to supernormal levels of PG and protein synthesis. Cartilage damaged to the extent of removal of over 50% of the total PG did not replace PG after over 4 weeks in 10% serum-Dulbecco's modified Eagle minimum with or without added TGF-b1 and rIGF-a. These data show that while the effects of Fn-f on elevating protease expression and depressing PG synthesis are reversible, the resultant cartilage damage is apparently irreversible in vitro. Therefore, if Fn-f-mediated cartilage damage occurs as part of cartilage disease processes, the pathologic effects would be quite significant.

Animals↗