PubMed Health⌕ Search

Biomedical subjects

C W McIlwraith

Publications and source records attributed to C W McIlwraith.

At least 19 recordsLinked to original sources

A comparative study of articular cartilage thickness in the stifle of animal species used in human pre-clinical studies compared to articular cartilage thickness in the human knee.

Histological measurements of the thickness of non-calcified and calcified cartilage, as well as the subchondral bone plate in five locations on the femoral trochlea and medial femoral condyles of species were used in preclinical studies of articular cartilage and compared to those of the human knee. Cadaver specimens were obtained of six human knees, as well as six equine, six goat, six dog, six sheep and six rabbit stifle joints (the animal equivalent of the human knee). Specimens were taken from the lateral trochlear ridge, medial trochlear ridge and medial femoral condyle. After histopathological processing, the thickness of non-calcified and calcified cartilage layers, as well as the subchondral bone plate, was measured. Average articular cartilage thickness over five locations were 2.2-2.5 mm for human, 0.3 mm for rabbit, 0.4-0.5 mm for sheep, 0.6-1.3 mm for dog, 0.7-1.5 mm for goat and 1.5-2 mm for horse. The horse provides the closest approximation to humans in terms of articular cartilage thickness, and this approximation is considered relevant in pre-clinical studies of cartilage healing.

Animals↗

Gene-mediated restoration of cartilage matrix by combination insulin-like growth factor-I/interleukin-1 receptor antagonist therapy.

Combination of growth factor gene-enhanced cartilage matrix synthesis with interleukin-1 receptor antagonist protein (IL-1Ra) abrogation of cartilage matrix degradation may reduce and possibly reverse cartilage loss in synovitis and osteoarthritis. The feasibility of cotransduction of synovial membrane with two such genes that may act on cartilage homeostasis was investigated in an in vitro coculture system. Cultured synoviocytes in monolayer were cotransduced with E1-deleted adenoviral vectors, one containing IGF-I coding sequence under cytomegalovirus (CMV) promoter control (200 multiplicities of infection (moi)), and the second containing IL-1Ra sequence under CMV promoter control (100 moi). Adenovirus-IGF-I (AdIGF-I) transduction and AdIGF-I/AdIL-1Ra cotransduction of synovial monolayer cultures resulted in increased IGF-I mRNA and ligand expression, and similarly AdIL-1Ra and AdIGF-I/AdIL-1Ra-transduced cultures expressed high levels of IL-1Ra. Northern analysis confirmed a single mRNA transcript of the appropriate size for both IGF-I and IL-1Ra transgene expression. Synovial cell monolayer and cartilage explant coculture experiments were used to examine the effects of IGF-I and IL-1Ra protein expressed by transduced synoviocytes on normal and IL-1-depleted cartilage. Transduced monolayer cultures produced peak medium IGF-I content of 114+/-20.2 ng/ml and IL-1Ra levels of 241.8+/-10.5 ng/ml at 48 h after transduction. These IGF-I concentrations were sufficient to produce significantly increased proteoglycan (PG) content of normal cartilage cultured in medium conditioned by AdIGF-I and AdIGF-I/AdIL-1Ra-transduced synoviocytes. Interleukin-1-exposed cartilage was markedly depleted of PG, and this catabolic state was partially reversed in AdIGF-I-transduced cultures and fully reversed by AdIGF-I/AdIL-1Ra-transduced synovial cocultures. These data indicate that cultured synoviocytes are readily cotransduced by two recombinant adenoviral vectors containing transgenes active in restoring joint health. The AdIL-1Ra and AdIGF-I transgenes were abundantly expressed and the secreted products achieved therapeutic concentrations by day 2. The resulting increase in matrix biosynthesis returned cartilage PG content to normal levels. These data suggest that there may be significant value in cotransduction of synovial membrane to attenuate cartilage malacia associated with synovitis, injury, or early arthritis.

Adenoviridae↗

Effects of glucosamine hydrochloride and chondroitin sulphate, alone and in combination, on normal and interleukin-1 conditioned equine articular cartilage explant metabolism.

REASONS FOR PERFORMING STUDY: Clinical trials in human and veterinary literature have documented the benefits of oral nutraceutical joint supplements containing glucosamine (GU) and chondroitin sulphate (CS) to treat mild to moderate osteoarthritis, but the effects of these components have not yet been conclusively determined. OBJECTIVES: To assess varying dosages of GU and CS on normal and interleukin-1alpha (IL-1) conditioned equine cartilage explants and rationalise the use of these products. HYPOTHESIS: Treatment would not be detrimental to cartilage metabolism and higher dosages and the combination of GU and CS would be more beneficial than lower dosages and. GU or CS alone. METHODS: Articular cartilage explants collected from the femoral trochlea and condyles were cultured in normal and IL-1 conditioned media. Treatment groups included 0, 12.5, 25,125 and 250 microg/ml concentrations of GU alone, CS alone, or GU+CS in combination. Glycosaminoglycan (GAG) synthesis and total GAG content in the explants and media were analysed. RESULTS: There were no detrimental effects of GU, CS or GU+CS on cartilage metabolism. High dosages of GU+CS reduced total GAG release into the media (degradation). CONCLUSIONS: Our results suggests that GU+CS may prevent cartilage GAG degradation. POTENTIAL RELEVANCE: The combination of GU and CS may be more effective in preventing or treating osteoarthritis in horses than either product alone.

Animals↗

The role of conformation in musculoskeletal problems in the racing Thoroughbred.

REASONS FOR PERFORMING STUDY: The relationship of conformation to future potential injury is a standard approach in practise but, at present, is largely based on subjective observations. OBJECTIVE: To measure conformation in 3-year-old Thoroughbreds and objectively test its relationship with the occurrence of musculoskeletal problems. METHODS: Conformation measurements were taken from photographs using specific reference points marked on the horses and processed on the computer. Clinical observations were recorded for each horse on a regular basis. Stepwise (forward) logistic regression analysis was performed to investigate the relationship between the binary response of the clinical outcomes probability and the conformation variables by the method of maximum likelihood. RESULTS: Clinical outcomes significantly (P<0.05) associated with conformational variables included effusion of the front fetlock, effusion of the right carpus, effusion of the carpus, effusion of the hind fetlock, fracture of the left or right carpus, right front fetlock problem and hind fetlock problem. CONCLUSIONS: Offset knees (offset ratio) contributed to fetlock problems. Long pasterns increased the odds of a fracture in the front limb. An increase in the carpal angle as viewed from the front (carpal valgus) may serve as a protective mechanism, as the odds for a carpal fracture and carpal effusion decreased with an increase in the carpal angle. POTENTIAL RELEVANCE: This study demonstrates relationships between conformation and musculoskeletal disease in the racehorse. The information may be useful in selection and management of the racing Thoroughbred.

Animals↗

Longitudinal development of equine conformation from weanling to age 3 years in the Thoroughbred.

REASONS FOR PERFORMING STUDY: There is little information available to define conformational changes with age using an objective but practical method of recording specific body measurements. OBJECTIVE: To analyse conformation objectively in a population of racing Thoroughbreds and describe the changes from weanling to age 3 years. METHODS: Annual photographs were taken over 4 years and conformation measurements made from photographs using specific reference points marked on the horses. RESULTS: Correlation analysis revealed highly significant, moderate to strong relationships between long bone lengths and wither height for all ages. All long bone lengths showed moderate to strong relationships with each other for all ages. The front and rear pastern angles were significantly correlated with the angle of the dorsal surface of the front and rear hooves, respectively, for all. Wither height, croup height and length of neck topline, neck bottomline, scapula, humerus, radius and femur increased significantly from age 0-1 year and age 1-2 years. Hoof lengths (medial and lateral, right and left) grew significantly between the ages of 0 and 1 and 1 and 2 years, but decreased in length between age 2 and 3 years. Horses became more offset in the right limb between weanling and age 3 years, but the offset ratios did not change with age on the left limb. The angle of the scapula (I), shoulder and radiometacarpus significantly increased between all age groups (became more upright). The angle of the dorsal surface of the hooves (both front and hind) decreased significantly from ages 0 to 1 and 1 to 2 years, but showed no significant difference between ages 2 and 3 years. CONCLUSIONS: A strong relationship between long bone lengths and wither height for all ages supports the theory that horses are proportional. Longitudinal bone growth in the distal limb increased only 5-7% from weanling to age 3 years and is presumably completed prior to the yearling year. Several growth measures increased from ages 0 to 1 and 1 to 2 years, but did not increase from age 2-3 years; indicating that growth rate either slowed or reached a plateau at this time. POTENTIAL RELEVANCE: This study provides objective information regarding conformation and skeletal growth in the Thoroughbred which can be utilised for selection and recognition of significant conformational abnormalities.

Aging↗

A dose titration of triamcinolone acetonide on insulin-like growth factor-1 and interleukin-1-conditioned equine cartilage explants.

REASONS FOR PERFORMING STUDY: Previous in vitro pilot studies have defined a potentially beneficial effect of insulin-like growth factor-1 (IGF-1) and triamcinolone acetonide (TA) on interleukin-1 (IL-1)-conditioned equine cartilage. Furthermore, an optimal dose for IGF-1 treatment alone has been documented previously using the same test system as in the current project. OBJECTIVES: To perform a dose titration of TA on IL-1-conditioned equine articular cartilage explants in the presence of an optimised IGF-1 dose, in order to optimise a triamcinolone concentration for use in combination with IGF-1 for future investigations. METHODS: Cartilage explants were harvested from the distal femur of a normal horse. The effect of a clinically relevant TA dose range was evaluated in the presence of IL-1 and IGF-1 through measurement of proteoglycan (PG) matrix metabolism (synthesis and degradation). RESULTS: TA and IGF-1 in combination inhibited the IL-1-induced release of PG matrix components (glycosaminoglycan or GAG) from the articular cartilage, as well as producing a significant increase in GAG synthesis. CONCLUSIONS: This experiment provided proof of principle that a combination treatment appears to be able to combat the IL-1-induced matrix depletion, while enhancing anabolic metabolism within the articular cartilage. POTENTIAL RELEVANCE: The use of IGF-1 in conjunction with TA in vivo has the potential to provide beneficial anabolic effects not seen with TA alone.

Animals↗

Significant exercise-related changes in the serum levels of two biomarkers of collagen metabolism in young horses.

OBJECTIVE: To identify metabolic biomarkers that can be evaluated in serum for monitoring the effects of exercise on skeletal development in mammals. DESIGN: Sera of foals from three groups (box-stall rest, pasture and training) were serially collected over the first 5 months of life and assayed for eight biomarkers of cartilage and bone metabolism. Sub-populations from each group were sampled for an additional 6 months of identical exercise. RESULTS: When expressed as a percentage of baseline values, lower serum levels of the carboxy-terminal propeptides of type II collagen (CPII), and higher serum levels of the cross-linked telopeptide fragments of degraded type I collagen (CTx1) were found in the trained foals compared to the other groups. Significant differences disappeared in those foals sampled during an additional 6 months of identical exercise. The most significant correlations were between serum biomarkers of bone metabolism, being positive between anabolic markers and negative between anabolic and catabolic markers. Serum levels of CTx1 and CPII significantly increased with age in all groups throughout the study. CONCLUSIONS: We have identified two markers of collagen metabolism, CPII and CTx1, as potential serum indicators of the exercise effects on the developing skeletal system in horses. Forced exercise during the first months postpartum appeared to have a negative effect on collagen turnover when compared to levels in pastured foals. Routine monitoring of collagen biomarkers in sera of exercising young mammals may allow for the early detection of abnormalities in skeletal tissue metabolism and for subsequent intervention before permanent damage occurs.

Aging↗

Effects of dosage titration of methylprednisolone acetate and triamcinolone acetonide on interleukin-1-conditioned equine articular cartilage explants in vitro.

REASONS FOR PERFORMING STUDY: Osteoarthritis is a frequent sequela of joint disease, especially with severe injuries or if attempts at therapy are unsuccessful. Negative and positive effects of corticosteroid treatment of articular cartilage have been demonstrated by in vitro and in vivo studies. OBJECTIVES: To assess the metabolic effects of varying dosages of methylprednisolone acetate (MPA) and triamcinolone acetonide (TA) on interleukin-1alpha (IL-1) conditioned equine cartilage explants. Our hypothesis was that lower dosages of corticosteroids would be less detrimental to cartilage metabolism than higher dosages. TA would be less detrimental to cartilage metabolism than MPA. METHODS: Treatment groups included articular cartilage explants with no IL-1 (control), IL-1 alone, and IL-1 plus 10, 5, 1 and 0.5 mg/ml MPA or 1.2, 0.6, 0.12 and 0.06 mg/ml TA. Explants were labelled with 35SO4 prior to the beginning and end of the experiment to assess glycosaminoglycan (GAG) degradation and synthesis, respectively. Total GAG content in media and explants and total cartilage DNA were also analysed. RESULTS: MPA and TA reduced GAG synthesis compared to control and IL-1 alone. The highest dosage of MPA (10 mg/ml) reduced GAG synthesis less than lower dosages of MPA and all dosages of TA. Compared to IL-1 alone, all dosages of TA and lower dosages of MPA increased GAG degradation. MPA at 10 mg/ml reduced GAG degradation. Both MPA and TA increased media GAG content compared to control and IL-1 explants. Total cartilage GAGs were unchanged with MPA, but reduced with TA, compared with IL-1 alone. Total cartilage DNA was decreased with MPA and increased with TA compared to IL-1 and control explants. CONCLUSIONS: MPA and TA did not counteract the negative effects of IL-1 and did not maintain cartilage metabolism at control levels. Lower dosages of MPA and TA were not less detrimental to cartilage metabolism than higher dosages. TA did not appear to be less harmful than MPA on cartilage metabolism. The results of this study differ from the findings of comparable in vivo studies. POTENTIAL RELEVANCE: The low numbers of horses used in this study limits extrapolation of these findings to the equine population; however, this study also questions the clinical relevance of this in vitro model.

Animals↗

Radiographic changes in Thoroughbred yearlings. Part 1: Prevalence at the time of the yearling sales.

REASONS FOR PERFORMING STUDY: Radiography in presale examinations of TB yearlings has become standard practice in recent years. OBJECTIVES: To describe the prevalence and distribution of radiographic changes in the fetlocks, carpi, tarsi, stifles and fore feet of Thoroughbred yearlings in central Kentucky when these joints were examined as part of routine pre- and post sale evaluations. METHODS: Horses subjected to radiographs included the fore (n = 1127) and hind (n = 1102) fetlocks, carpi (n = 1130), tarsi (n = 1101), stifles (n = 660) and fore feet (n = 300). Radiographic changes were categorised by location and type of change present (e.g. lucency, fragment) for each series. RESULTS: In the fore fetlocks 1.6% had fragmentation of the proximal dorsal first phalanx and 0.5% fragmentation of the proximal palmar aspect. In the hind fetlocks 5.9% had fragmentation at the plantar aspect and 3.3% fragmentation dorsally. Lucencies, fragments or loose bodies were detected at the dorsal aspect of the distal third metacarpus in 2.8% and, at the same location on the third metatarsus, 3.2%. Most yearlings (98%) had vascular channels in the proximal sesamoid bones and irregular vascular channels (> 2 mm wide or with nonparallel sides) were more common (79%) than regular vascular channels (56%). The intermediate ridge of the distal tibia was the most common location for fragmentation in the tarsus (4.4%). CONCLUSIONS: While some radiographic changes, e.g. vascular channels in proximal sesamoid bones, are very common in Thoroughbred yearlings, others, e.g. fragmentation or subchondral lucency within joints are quite rare usually affecting less than 5% of the population. POTENTIAL RELEVANCE: Veterinarians should expect to find radiographic changes in Thoroughbreds presented for examination prior to the yearling sales. The rarity of some changes thought to affect soundness or racing performance will make further invesigation of these conditions in horses without clinical signs more difficult.

Animals↗

Radiographic changes in Thoroughbred yearlings. Part 2: Associations with racing performance.

REASONS FOR PERFORMING STUDY: Although the radiographic examination of yearlings has become commonplace at some large Thoroughbred sales, there are few data to support the decisions facing veterinarians who are asked to evaluate future racing potential. OBJECTIVES: To identify radiographic changes in the fetlocks, proximal sesamoid bones, carpi, tarsi, stifles and fore feet of Thoroughbred yearlings associated with future racing performance during ages 2 and 3 years. METHODS: Radiographs from routine pre- and post sale examinations of 1162 yearlings were used to identify individual radiographic changes in sale yearlings. Starting a race, the percent of starts placed, money earned and earnings per start were used to assess racing performanceand examined for associations with the radiographic changes observed. RESULTS: Overall 946 (81%) yearlings started at least one race during ages 2 or 3 years. Fourteen of 24 (58%) yearlings with moderate or extreme palmar supracondylar lysis of the third metacarpus, 8 of 14 (57%) of those with enthesophyte formation on the proximal sesamoid bones and 19 of 30 (63%) of those with dorsal medial intercarpal joint disease started a race. The odds of starting a race when age 2 or 3 years were 3 times lower for yearlings with these changes (P < 0.01) compared with yearlings that did not have these changes. Twenty-five of 36 (69%) yearlings with proximal dorsal fragmentation of the first phalanx in the hind fetlock started a race and these yearlings were also less likely (OR = 0.51, P = 0.07) to start a race. Yearlings with enthesophyte formation on hind proximal sesamoid bones placed in a smaller percentage of starts (16%, P = 0.01) earned less money (987 US dollars, P = 0.02) and had lower earnings per start (252 US dollars, P = 0.03) compared to starters without this change. CONCLUSIONS: Although many of the changes observed on radiographs of sale yearlings do not appear to influence future racing performance, some are associated with reduced performance. POTENTIAL RELEVANCE: The results of this study are best applied in parallel with the clinical impressions of veterinarians experienced in examining radiographs of sale yearlings. Some findings support those established in the literature as incidental findings and others suggest new areas for concern not previously reported as a problem in Thoroughbred sale yearlings.

Animals↗

Treatment of experimental equine osteoarthritis by in vivo delivery of the equine interleukin-1 receptor antagonist gene.

Osteoarthritis in horses and in humans is a significant social and economic problem and continued research and improvements in therapy are needed. Because horses have naturally occurring osteoarthritis, which is similar to that of humans, the horse was chosen as a species with which to investigate gene transfer as a potential therapeutic modality for the clinical treatment of osteoarthritis. Using an established model of equine osteoarthritis that mimics clinical osteoarthritis, the therapeutic effects resulting from intra-articular overexpression of the equine interleukin-1 receptor antagonist gene through adenoviral-mediated gene transfer were investigated. In vivo delivery of the equine IL-IRa gene led to elevated intra-articular expression of interleukin-1 receptor antagonist for approximately 28 days, resulting in significant improvement in clinical parameters of pain and disease activity, preservation of articular cartilage, and beneficial effects on the histologic parameters of synovial membrane and articular cartilage. Based on these findings, gene transfer of interleukin-1 receptor antagonist is an attractive treatment modality for the equine patient and also offers future promise for human patients with osteoarthritis.

Adenoviridae↗

Gene therapy: future therapies in osteoarthritis.

The field of equine veterinary practice is in an ever-evolving state, requiring current technologies to be constantly evaluated for new applications. The specific use of gene therapy in the horse is a novel application. The authors want to help familiarize the equine practitioner with the concept of gene therapy, and introduce its use and potential future benefits for the equine industry in the treatment of osteoarthritis.

Animals↗

The role of subchondral bone in joint disease: a review.

Subchondral bone plays a role in the pathogenesis of osteochondral damage and osteoarthritis in horses and humans. Osteochondral fragmentation and fracture, subchondral bone necrosis and osteoarthritis are common diseases in athletic horses, and subchondral bone is now thought to play an integral role in the pathogenesis of these diseases. There have been numerous research efforts focused on articular cartilage damage and its pathogenesis, yet comparatively little effort focused on subchondral bone pathology or the coordinated disease states of the osteochondral tissues. The purpose of this report is to review the current understanding of osteochondral disease in all species and its application to equine research and practice. It can be concluded from this review that our current understanding of osteochondral disease is based on clinical and pathological sources; and that the lack of information about joint tissue adaptation and disease has hampered objective studies of osteochondral tissues.

Animals↗

Upregulation of mRNA of interleukin-1 and -6 in subchondral cystic lesions of four horses.

This study investigated the potential association of interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) in subchondral cystic lesions (SCL) in horses. With the technique of in situ hybridisation in paraffin sections of fibrous tissue of SCL and quantitative real-time PCR in fresh frozen fibrous tissue and undecalcified bone sections of SCL embedded in acrylic resin, upregulation of mRNA of both cytokines could be demonstrated. mRNA of IL-1beta was upregulated at the periphery of the cystic lesion adjacent to normal bone, whereas IL-6 mRNA was upregulated within the fibrous tissue found within the centre of the SCL. It was concluded that both cytokines are associated in pathological bone resorption observed in SCL and, in combination with increased production of prostaglandin E2, may be responsible for the slow healing, maintenance or further expansion of the cystic lesions.

Animals↗

Use of an antineoepitope antibody for identification of type-II collagen degradation in equine articular cartilage.

OBJECTIVE: To develop an antibody that specifically recognizes collagenase-cleaved type-II collagen in equine articular cartilage. SAMPLE POPULATION: Cartilage specimens from horses euthanatized for problems unrelated to the musculoskeletal system. PROCEDURE: A peptide was synthesized representing the carboxy- (C-) terminus (neoepitope) of the equine type-II collagen fragment created by mammalian collagenases. This peptide was used to produce a polyclonal antibody, characterized by western analysis for reactivity to native and collagenase-cleaved equine collagens. The antibody was evaluated as an antineoepitope antibody by ELISA, using peptides +/- an amino acid at the C-terminus of the immunizing peptide. Collagen cleavage was assayed from equine articular cartilage cultured with interleukin-1 (IL-1), +/- a synthetic MMP inhibitor, BAY 12-9566. Cartilage specimens from osteoarthritic and nonarthritic joints were compared for antibody staining. RESULTS: An antibody, 234CEQ, recognized only collagenase-generated 3/4-length fragments of equine type-II collagen. This was a true antineoepitope antibody, as altering the C-terminus of the immunizing peptide significantly decreased competition for binding in an inhibition ELISA. The IL-1-induced release of type-II collagen fragments from articular cartilage was prevented with the MMP inhibitor. Cartilage from an osteoarthritic joint of a horse had increased staining with the 234CEQ antibody, compared with normal articular cartilage. CONCLUSIONS AND CLINICAL RELEVANCE: We generated an antineoepitope antibody recognizing collagenase-cleaved type-II collagen of horses. This antibody detects increases in type-II collagen cleavage in diseased equine articular cartilage. The 234CEQ antibody has the potential to aid in the early diagnosis of arthritis and to monitor treatment responses.

Animals↗

Synovial fluid gelatinase concentrations and matrix metalloproteinase and cytokine expression in naturally occurring joint disease in horses.

OBJECTIVES: To determine concentrations of matrix metalloproteinase (MMP)-2 and -9 in synovial fluid; and mRNA expression of MMP-1, -13, and -3; interleukin[IL]-1alpha and beta; and tumor necrosis factor (TNF)-alpha in synovial membrane and articular cartilage from horses with naturally occurring joint disease. SAMPLE POPULATION: Synovial fluid (n = 76), synovial membrane (59), and articular cartilage (45) from 5 clinically normal horses and 55 horses with joint disease categorized as traumatic (acute [AT] or chronic [CT]), osteochondritis dissecans (OCD), or septic (S). PROCEDURE: Synovial fluid gelatinase concentrations were analyzed, using zymography. Synovial membrane and articular cartilage mRNA expression for MMP-1, -3, and -13, IL-1alpha and beta, TNF-alpha, type-II collagen, and aggrecan were analyzed, using quantitative reverse transcriptase-polymerase chain reaction. RESULTS: Synovial fluid pro-MMP-2 concentration was significantly higher in diseased joints than normal joints. Septic joints had significantly higher concentrations of pro and active MMP-9. Stromelysin-1 was expressed in > or = 80% of synovial membrane and articular cartilage samples and was strongly influenced by age. Collagenases were rarely expressed, with MMP-13 expressed only in diseased joints. Interleukin-1beta expression was significantly higher in all OCD samples and was influenced by age. Tumor necrosis factor-alpha expression was significantly higher in cartilage from joints with AT and OCD. There was no correlation between MMP or cytokines and type-II collagen or aggrecan expression. CONCLUSIONS AND CLINICAL RELEVANCE: Matrix metalloproteinase-2 and -3 are abundant in naturally occurring joint disease and normal joints. Interleukin-1beta and TNF-alpha may be important in the pathogenesis of OCD. Age affects MMP and IL-1beta concentrations.

Animals↗