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Beckett J.,Saint Louis University | Jin W.,Saint Louis University | Schultz M.,Saint Louis University | Chen A.,Saint Louis University | And 4 more authors.
Journal of Orthopaedic Research | Year: 2012

The goal of this study was to develop an aggressive running regimen for modeling osteoarthritis (OA) in rats. Twelve Wistar rats were randomly placed into either a running group or a non-running group to serve as the control. The running rats used a motorized treadmill to run either 30 km in 3 weeks or 55 km in 6 weeks. Each week, the prints of hind paws were obtained when rats were made to walk through a tunnel. The resulting prints were digitalized for analyses of stride length and step angle. The histology of the knees was examined at 3 and 6 weeks and the OA pathology in the knees was quantified by Mankin's score. Osteoarthritic pathology developed in the knees of the running rats, including decreased proteoglycan content, uneven type II collagen distribution in the cartilage matrix, increased MMP-13 expression, expanded calcified cartilage zone, and clefts and defects in articular cartilage. The pathology worsened from running for 3 to 6 weeks. Gait analysis revealed an inverse correlation between paw angle and the grades of OA pathology. In conclusion, excessive running induces joint degeneration and a unique gait pattern in rats. © Copyright © 2012 Orthopaedic Research Society.


Foo T.,Saint Louis University | Reagan J.,Saint Louis University | Watson J.T.,Saint Louis University | Moed B.R.,Saint Louis University | Zhang Z.,Orthobiologic Laboratory
Journal of Tissue Engineering | Year: 2013

An appropriate animal model is critical for the research of stem/progenitor cell therapy and tissue engineering for bone regeneration in vivo. This study reports the design of an external fixator and its application to critical-sized femoral defects in athymic rats. The external fixator consists of clamps and screws that are readily available from hardware stores as well as Kirschner wires. A total of 35 rats underwent application of the external fixator with creation of a 6-mm bone defect in one femur of each animal. This model had been used in several separate studies, including implantation of collagen gel, umbilical cord blood mesenchymal stem cells, endothelial progenitor cells, or bone morphogenetic protein-2. One rat developed fracture at the proximal pin site and two rats developed deep tissue infection. Pin loosening was found in nine rats, but it only led to the failure of external fixation in two animals. In 8 to 10 weeks, various degrees of bone growth in the femoral defects were observed in different study groups, from full repair of the bone defect with bone morphogenetic protein-2 implantation to fibrous nonunion with collagen gel implantation. The external fixator used in these studies provided sufficient mechanical stability to the bone defects and had a comparable complication rate in athymic rats as in immunocompetent rats. The external fixator does not interfere with the natural environment of a bone defect. This model is particularly valuable for investigation of osteogenesis of human stem/progenitor cells in vivo. © The Author(s) 2013.


Schultz M.,Saint Louis University | Molligan J.,Orthobiologic Laboratory | Schon L.,Orthobiologic Laboratory | Zhang Z.,Orthobiologic Laboratory
PLoS ONE | Year: 2015

Objectives: This study aimed to investigate the pathology occurring at the calcified zone of articular cartilage (CZC) in the joints afflicted with post-traumatic osteoarthritis (PTOA). Methods: Rats underwent bilateral anterior cruciate ligament (ACL) transection and medial meniscectomy to induce PTOA. Sham surgery was performed on another five rats to serve as controls. The rats were euthanized after four weeks of surgery and tibial plateaus were dissected for histology. The pathology of PTOA, CZC area and the tidemark roughness at six pre-defined locations on the tibial plateaus were quantified by histomorphometry. Results: PTOA developed in the knees, generally more severe at the medial plateau than the lateral plateau, of rats in the experimental group. The CZC area was unchanged in the PTOA joints, but the topographic variations of CZC areas that presented in the control knees were reduced in the PTOA joints. The tidemark roughness decreased in areas of the medial plateau of PTOA joints and that was inversely correlated with the Mankin's score of PTOA pathology. Conclusion: Reduced tidemark roughness and unchanged CZC area differentiate PTOA from primary osteoarthritis, which is generally believed to have the opposite pathology at CZC, and may contribute to the distinct disease progression of the two entities of arthropathy. © 2015 Schultz et al.


Molligan J.,Orthobiologic Laboratory | Mitchell R.,Orthobiologic Laboratory | Schon L.,Orthobiologic Laboratory | Achilefu S.,Washington University in St. Louis | And 4 more authors.
Stem Cells Translational Medicine | Year: 2016

By using surgical mouse models, this study investigated how the tissue environment influences the osteogenic potential of muscle progenitors (m-progenitors) and potentially contributes to heterotopic ossification (HO). Injury was induced by clamping the gluteus maximus and medius (group M) or osteotomy of greater trochanter (group O) on the right hip, as well as combined muscle injury and osteotomy of greater trochanter (group M+O). The gluteus maximus and medius of the operated hips were harvested at days 1, 3, 5, and 10 for isolation of m-progenitors. The cells were cultured in an osteogenic medium for 3 weeks, and osteogenesis was evaluated by matrix mineralization and the expression of osteogenesis-related genes. The expression of type I collagen, RUNX2 (runt-related transcription factor 2), and osteocalcin by the m-progenitors of group M+O was significantly increased, compared with groups M and O. Osteogenic m-progenitors in group O increased the expression of bone morphogenetic protein 2 and also bone morphogenetic protein antagonist differential screening-selected gene aberrative in neuroblastoma. On histology, there was calcium deposition mostly in the muscles of group M+O harvested at day 10. CD56, representing myogenic progenitors, was highly expressed in the m-progenitors isolated from group M (day 10), but m-progenitors of group M+O (day 10) exhibited the highest expression of platelet-derived growth factor receptor α (PDGFR-α), a marker of muscle-derived mesenchymal stem cells (M-MSCs). The expressions of PDGFR-a and RUNX2 were colocalized in osteogenic m-progenitors. The data indicate that the tissue environment simulated in the M+O model is a favorable condition for HO formation. Most likely, M-MSCs, rather than myogenic progenitors, in the m-progenitors participate in HO formation. © AlphaMed Press 2016.


Molligan J.,Orthobiologic Laboratory | Schon L.,Orthobiologic Laboratory | Zhang Z.,Orthobiologic Laboratory
Journal of Anatomy | Year: 2013

Plantar fat pad (PFP) is a tissue structure that absorbs the initial impact of walking and running and ultimately bears body weight at standing. This study was designed to quantify the histomorphological changes of the PFP in aged rats. The most medial PFP was dissected from the hind feet of young rats (4 months old, n = 6) and aged rats (24 months old, n = 6). Histological structure and cellular senescence of PFP were analyzed stereologically and histomorphometrically. Immunohistochemistry of matrix metalloproteinase 9 (MMP9) was also performed on PFP tissue sections. Compared with young rats, the thickness of epidermis, dermis and septa of the PFP were significantly reduced in the aged rats. The total volume of adipose tissue in the PFP of aged rats was only about 65% of that in the young rats. The microvascular density and the number of fat pad units (FPU), a cluster of adipocytes enclosed by elastin septa, in the PFP were unchanged in the aged rats. In the aged rats, the number of adipocytes per FPU was reduced but the number of simple adipocyte clusters, without surrounding septa, was increased. The shift of the types of adipocyte clusters in the aged PFP was accompanied by degradation of elastin fibers and increased expression of MMP9. In conclusion, the PFP, particularly the elastic septa, degenerates significantly in aged rats and this may contribute to the pathology of PFP-related diseases. © 2013 Anatomical Society.

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