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- Author or Editor: David D. Frisbie x
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Abstract
Objective
To evaluate potential stimulatory or matrixsparing effects of insulin-like growth factor 1 (IGF-1 ), alone or in combination with a corticosteroid, in an interleukin 1 (IL-1)-induced model of cartilage degradation.
Samples
Cartilage from the weightbearing surfaces of trochlea and condyles of clinically normal 2-year-old male horses.
Procedure
Triamcinolone acetonide and IGF-1 effects were evaluated by assessing: matrix responses by sulfated glycosaminoglycan (GAG) assay and [35S]sulfated GAG synthesis; collagen content by hydroxyproline assay; and mitogenic response by [3H]thymidine incorporation into DNA and fluorometric assay of total DNA concentration.
Results
Conditioning of cartilage expiants with 10 ng of human recombinant IL-1α increased degradation and decreased synthesis of matrix proteoglycans (PG), without affecting matrix collagen content. Human recombinant IGF-1 decreased PG loss and reversed the reduction of PG synthesis in cartilage expiants conditioned with IL-1. Given alone, steroids decreased PG concentration and synthetic rate in normal cartilage. However, the previously diminished PG content, attributable to IL-1 conditioning, was not further exacerbated by steroid administration in IL-1-conditioned expiants. Combined treatment of normal cartilage expiants with IGF-1 and steroids resulted in PG preservation and increase in collagen content. Similar PG and collagen effects were not evident when treating IL-1-conditioned cartilage with IGF-1/steroid combinations. Decrease in chondrocyte proliferation was associated with steroid administration. Exposure to IGF and steroids prevented the decrease in mitogenesis that could lead to cellular loss, particularly in IL-1-conditioned expiants.
Conclusion
Combination IGF-1 and steroid treatment of normal cartilage cultures indicated substantial ability to override the anabolic suppression associated with steroids alone. Potentially, administration of corticosteroids, followed by IGF-1, may act to decrease propagation of detrimental mediator release while allowing appreciation of the chondroenhancing effects of IGF-1. These beneficial effects were considerably reduced in IL-1-induced cartilage damage. (Am J Vet Res 1997;58:524–530)
Abstract
Objective—To compare the mesenchymal stem cell (MSC) yield and chondrogenic and osteogenic differentiation from 5- and 50-mL bone marrow aspirates from horses.
Animals—Six 2- to 5-year-old mixed-breed horses.
Procedures—2 sequential 5-mL aspirates were drawn from 1 ilium or sternebra. A single 50-mL aspirate was drawn from the contralateral ilium, and 2 sequential 50-mL aspirates were drawn from a second sternebra. The MSC yield was determined through the culture expansion process. Chondrogenesis and osteogenesis were evaluated by means of conventional laboratory methods.
Results—The second of the 2 sequential 50-mL sternal aspirates yielded few to no MSCs. Independent of location, the highest density of MSCs was in the first of the 2 sequential 5-mL fractions, although with subsequent culture expansion, the overall yield was not significantly different between the first 5-mL and first 50-mL fractions. Independent of location, chondrogenesis and osteogenesis were not significantly different among fractions. Independent of fraction, the overall cell yield and chondrogenesis from the ilium were significantly higher than that from the sternum.
Conclusions and Clinical Relevance—This study failed to detect an additional benefit of 50-mL aspirates over 5-mL aspirates for culture-expanding MSCs for equine clinical applications. Chondrogenesis was highest for MSCs from ilial aspirates, although it is not known whether chondrogenesis is indicative of activation of other proposed pathways by which MSCs heal tissues.
Abstract
Objective—To assess the clinical, biochemical, and histologic effects of extracorporeal shock wave therapy (ESWT) in the treatment of horses with experimentally induced osteoarthritis (OA).
Animals—Twenty-four 2- to 3-year-old horses without evidence of lameness.
Procedures—OA was induced arthroscopically in 1 middle carpal joint of each horse. Fourteen days after induction of OA, horses were treated with a sham ESWT probe (placebo; n = 8), polysulfated glycosaminoglycan (PSGAG) administered IM every 4 days for 28 days as a positive control treatment (8), or ESWT administered on days 14 and 28 with a focused shock wave unit (8). Evaluations included clinical assessments of degree of lameness every 2 weeks and weekly synovial fluid analyses. Horses were euthanized 70 days after induction of OA, and gross pathologic and histologic examinations of cartilage and synovial membrane specimens were performed at necropsy. A generalized linear mixed model was used to compare outcomes among treatment groups.
Results—No adverse treatment-related events were detected in any horse. The degree of lameness in horses treated with ESWT improved significantly, compared with the degree of lameness in placebo- or PSGAG-treated horses. No disease-modifying effects were evident in results for synovial fluid, synovial membranes, or cartilage from the ESWT- or PSGAG-treated horses.
Conclusions and Clinical Relevance—Although a disease-modifying effect of ESWT was not detected, the significant clinical effect of ESWT suggested that this modality should be considered for treatment of horses with OA in combination with another modality that does affect the disease process.
Abstract
Objective—To evaluate effects of extracorporeal shock wave therapy (ESWT) and polysulfated glycosaminoglycan treatment (PSGAGT) on subchondral bone (SCB), serum biomarkers, and synovial fluid biomarkers in horses with induced osteoarthritis.
Animals—24 healthy 2- to 3-year-old horses.
Procedures—An osteochondral fragment was created on the distal aspect of the radial carpal bone in 1 middle carpal joint of each horse. Horses were randomly allocated to receive local application of ESWT (days 14 and 28; n = 8), PSGAGT (IM, q 4 d for 28 days; 8), or a sham ESWT probe (placebo; days 14 and 28; 8). Serum biomarkers were measured every 7 days, and synovial fluid biomarkers were measured every 14 days. Bone density was measured by use of computed tomography on days 0 and 70, and microdamage and bone formation variables were compared among groups at the end of the study (day 70).
Results—There was no significant effect of ESWT or PSGAGT on any bone variable. Serum osteocalcin concentration was significantly greater in horses that received ESWT, compared with placebo-treated horses, and serum concentration of the C-terminal telopeptide of type I collagen was significantly higher in horses that received ESWT, compared with placebo- and PSGAG-treated horses. Concentrations of the synovial fluid epitope CS846 were significantly higher in joints with osteoarthritis treated with ESWT
Conclusions and Clinical Relevance—Treatment of osteoarthritis with ESWT had no effect on SCB but did induce increases in serum biomarkers indicative of bone remodeling. Treatment of osteoarthritis with PSGAG had no effect on SCB or biomarkers.
Abstract
Objective—To assess clinical, biochemical, and histologic effects of polysulfated glycosaminoglycan (PSGAG) or sodium hyaluronan administered intra-articularly in treatment of horses with experimentally induced osteoarthritis.
Animals—24 horses.
Procedures—Osteoarthritis was induced arthroscopically in 1 middle carpal joint of all horses. Eight horses received hyaluronan (20 mg) and amikacin (125 mg) intra-articularly on study days 14, 21, and 28. Eight horses received PSGAG (250 mg) and amikacin (125 mg) intra-articularly on study days 14, 21, and 28. Eight control horses received 2 mL of saline (0.9% NaCl) solution and amikacin (125 mg) intra-articularly on study days 14, 21, and 28. Clinical, radiographic, synovial fluid analysis, gross, histologic, histochemical, and biochemical findings were evaluated.
Results—No adverse treatment-related events were detected. Induced osteoarthritis caused a substantial change in lameness, response to flexion, joint effusion, and radiographic findings, and of these, synovial fluid effusion was reduced with PSGAG, compared with control horses. No changes in clinical signs were seen with PSGAG or hyaluronan, compared with control horses. Histologically, the degree of synovial membrane vascularity and subintimal fibrosis was significantly reduced with PSGAG treatment, compared with controls. Histologically, significantly less fibrillation was seen with hyaluronan treatment, compared with controls.
Conclusions and Clinical Relevance—Results indicated that PSGAG and hyaluronan had beneficial disease-modifying effects and are viable therapeutic options for osteoarthritis in horses.
Abstract
Objective—To assess clinical, radiographic, histologic, and biochemical effects of sodium pentosan polysulfate (NaPPS) administered IM for treatment of experimentally induced osteoarthritis in horses.
Animals—18 horses.
Procedures—Osteoarthritis was induced arthroscopically in 1 middle carpal joint of all horses. Nine horses received NaPPS (3 mg/kg, IM) on study days 15, 22, 29, and 36. Nine control horses received the same volume of saline (0.9% NaCl) solution IM on study days 15, 22, 29, and 36. Clinical, radiographic, gross, histologic, histochemical, and biochemical findings as well as findings of synovial fluid analysis were evaluated.
Results—No adverse treatment-related events were detected. Induced osteoarthritis caused a substantial increase in lameness, response to flexion, joint effusion, radiographic findings, synovial membrane inflammation, and articular cartilage fibrillation. Articular cartilage fibrillation was substantially reduced by NaPPS treatment, and concentrations of chondroitin sulfate 846 epitope were significantly increased in the synovial fluid of osteoarthritic and nonosteoarthritic joints of treated horses.
Conclusions and Clinical Relevance—Results indicated that NaPPS has some beneficial disease-modifying effects and may be a therapeutic option for osteoarthritis in horses.
Abstract
OBJECTIVE To evaluate the efficacy of IV administration of a product containing hyaluronan, sodium chondroitin sulfate, and N-acetyl-d-glucosamine for prevention or treatment of osteoarthritis in horses.
ANIMALS 32 healthy 2- to 5-year-old horses.
PROCEDURES The study involved 2 portions. To evaluate prophylactic efficacy of the test product, horses received 5 mL of the product (n = 8) or saline (0.9% NaCl) solution (8; placebo) IV every fifth day, starting on day 0 (when osteoarthritis was induced in the middle carpal joint of 1 forelimb) and ending on day 70. To evaluate treatment efficacy, horses received either the product or placebo (n = 8/treatment) on days 16, 23, 30, 37, and 44 after osteoarthritis induction. Clinical, diagnostic imaging, synovial fluid, gross anatomic, and histologic evaluations and other tests were performed. Results of each study portion were compared between treatment groups.
RESULTS Limb flexion and radiographic findings were significantly worse for horses that received the test product in the prophylactic efficacy portion than for placebo-treated horses or product-treated horses in the treatment efficacy portion. In the prophylactic efficacy portion, significantly less articular cartilage erosion was identified in product-treated versus placebo-treated horses. In the treatment efficacy portion, joints of product-treated horses had a greater degree of bone edema identified via MRI than did joints of placebo-treated horses but fewer microscopic articular cartilage abnormalities.
CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that caution should be used when administering the evaluated product IV to horses, particularly when administering it prophylactically, as it may have no benefit or may even cause harm.
Abstract
Objective—To evaluate the use of serum concentrations of biochemical markers of bone metabolism (osteocalcin [OC], bone-specific alkaline phosphatase [BS-ALP], and deoxypyridinoline [DPYR]) to compare healing in infected versus noninfected fractures and in fractures with normal repair versus delayed (nonunion) repair in rabbits.
Animals—32 female 9- to 10-month-old New Zealand White rabbits.
Procedure—A femoral fracture defect was made in each rabbit. Rabbits were assigned to the following groups: the bone morphogenetic-2 gene treatment group with either noninfected nonunion or infected (ie, inoculation of defects with Staphylococcus aureus) nonunion fractures or the luciferase (control) gene treatment group with either noninfected nonunion or infected nonunion fractures. Serum samples were obtained before surgery (time 0) and 4, 8, 12, and 16 weeks after surgery. Callus formation and lysis grades were evaluated radiographically at 16 weeks.
Results—Serum OC and BS-ALP concentrations decreased from time 0 at 4 weeks, peaked at 8 weeks, and then decreased. Serum DPYR concentration peaked at 4 weeks and then decreased, independent of gene treatment group or fracture infection status. Compared with rabbits with noninfected fractures, those with infected fractures had lower serum OC and BS-ALP concentrations at 4 weeks, higher serum OC concentrations at 16 weeks, and higher serum DPYR concentrations at 4, 8, and 16 weeks. Combined serum OC, BS-ALP, and DPYR concentrations provided an accuracy of 96% for prediction of fracture infection status at 4 weeks.
Conclusions and Clinical Relevance—Measurement of multiple serum biochemical markers of bone metabolism could be useful for clinical evaluation of fracture healing and early diagnosis of osteomyelitis. ( J Am Vet Med Assoc 2003;64:727–735)
Abstract
Objective—To determine response of interleukin-1α (IL-1α)-conditioned equine articular cartilage explants to insulin-like growth factor-1 (IGF-1).
Sample Population—Cartilage from the trochlea and condyles of the femur of a clinically normal 4-year-old horse.
Procedure—Effects of IGF-1 (0 to 500 ng/ml) after addition of IL-1α were evaluated by assessing matrix responses, using a sulfated glycosaminoglycan (GAG) assay, matrix 35SO4 GAG incorporation, and release of GAG. Mitogenic response was assessed by 3H-thymidine incorporation into DNA and fluorometric assay of total DNA concentration.
Results—Human recombinant IL-1α (40 ng/ml) increased the amount of labeled GAG released and decreased labeled and total GAG remaining in explants, and IL-1α decreased mitogenic response. Addition of IGF-1 counteracted effects seen with IL-1α alone. In general, IGF-1 decreased total and labeled GAG released into the medium, compared with IL-1α- treated explants (positive-control sample). Values for these variables did not differ significantly from those for negative-control explants. A significant increase in total and newly synthesized GAG in the explants at termination of the experiment was observed with 500 ng of IGF-1/ml. Labeled GAG remaining in explants was greater with treatment at 50 ng of IGF-1/ml, compared with treatment with IL-1α alone. Concentrations of 200 ng of IGF-1/ml abolished actions of IL-1α and restored DNA synthesis to values similar to those of negative-control explants.
Conclusions and Clinical Relevance—IGF-1 at 500 ng/ml was best at overcoming detrimental effects associated with IL-1α in in vitro explants. These beneficial effects may be useful in horses with osteoarthritis. (Am J Vet Res 2000;61:436–441)
