Preclinical Studies on Mesenchymal Stem Cell-Based Therapy for Growth Plate Cartilage Injury Repair

In the last two decades, there has been a strong interest in searching for biological treatments for regeneration of injured growth plate cartilage and prevention of its bony repair. Various means have been tried, including implantation of chondrocytes, mesenchymal stem cell (MSC), together with exogenous growth factor and scaffolds, and gene therapy. However, with the lack of success with chondrocytes, more research has focussed on MSC-based treatments. In addition to circumvent limitations with MSC-based treatments (including cell harvest-associated morbidity, difficulties/time/cost involved in MSC isolation and ex vivo expansion, and potential disease transmission), mobilising endogenous MSCs to the growth plate injury site and enhancing in situ regeneration mechanisms would represent an alternative attractive approach. Further studies are required to investigate the potential particularly in large animal models or clinical setting of the ex vivo MSC approach and the feasibility of the endogenous MSC in situ approach in growth plate regeneration

Methotrexate Toxicity in Growing Long Bones of Young Rats: A Model for Studying Cancer Chemotherapy-Induced Bone Growth Defects in Children

The advancement and intensive use of chemotherapy in treating childhood cancers has led to a growing population of young cancer survivors who face increased bone health risks. However, the underlying mechanisms for chemotherapy-induced skeletal defects remain largely unclear. Methotrexate (MTX), the most commonly used antimetabolite in paediatric cancer treatment, is known to cause bone growth defects in children undergoing chemotherapy. Animal studies not only have confirmed the clinical observations but also have increased our understanding of the mechanisms underlying chemotherapy-induced skeletal damage. These models revealed that high-dose MTX can cause growth plate dysfunction, damage osteoprogenitor cells, suppress bone formation, and increase bone resorption and marrow adipogenesis, resulting in overall bone loss. While recent rat studies have shown that antidote folinic acid can reduce MTX damage in the growth plate and bone, future studies should investigate potential adjuvant treatments to reduce chemotherapy-induced skeletal toxicities

Strain Amplification Analysis of an Osteocyte under Static and Cyclic Loading: A Finite Element Study

Copyright © 2015 Liping Wang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Osteocytes, the major type of bone cells which reside in their lacunar and canalicular system within the bone matrix, function as biomechanosensors and biomechanotransducers of the bone. Although biomechanical behaviour of the osteocyte-lacunar-canalicular system has been investigated in previous studies mostly using computational 2-dimensional (2D) geometric models, only a few studies have used the 3-dimensional (3D) finite element (FE) model. In the current study, a 3D FE model was used to predict the responses of strain distributions of osteocyte-lacunar-canalicular system analyzed under static and cyclic loads. The strain amplification factor was calculated for all simulations. Effects on the strain of the osteocyte system were investigated under 500, 1500, 2000, and 3000 microstrain loading magnitudes and 1, 5, 10, 40, and 100 Hz loading frequencies. The maximum strain was found to change with loading magnitude and frequency. It was observed that maximum strain under 3000-microstrain loading was higher than those under 500, 1500, and 2000 microstrains. When the loading strain reached the maximum magnitude, the strain amplification factor of 100 Hz was higher than those of the other frequencies. Data from this 3D FE model study suggests that the strain amplification factor of the osteocyte-lacunar-canalicular system increases with loading frequency and loading strain increasing

A three-dimensional finite element modelling of human chest injury following front or side impact loading

Based on anatomical features of a 50th percentile adult male, three-dimensional (3D) finite element (FE) models of ribs, sternum, vertebrae, intervertebral discs, clavicle, scapula, pelvis, skin, head, muscles and limbs were developed in this study. After integrating/assembling various organs and tissues, a bio-mechanical FE model of the human body with adult male characteristics was produced. Furthermore, a chest frontal and lateral collision theory model was built and was validated by using previously published data from corpse frontal and lateral chest impact collision experiments. Good agreements were found between the simulation results of our model and the experimental data as well as theoretical calculations in the contact force, sternum displacement, and force-displacement response. These data suggest that this 3D FE model is effective and has good bio-fidelity in assessing chest biomechanical responses and thoracic injuries upon impact loading. Therefore this model can potentially be useful for evaluating thoracic injuries in car crashes and assessing chest rib fractures and internal organ/tissue damages

HYDROXYMETHYL FURFURAL IN CHINESE HERBAL MEDICINES: ITS FORMATION, PRESENCE, METABOLISM, BIOACTIVITIES AND IMPLICATIONS

Hydroxymethyl furfural (HMF) is one of important intermediates formed in Maillard reaction and caramelization. It was found that HMF existed in many Chinese herbal medicines (CHMs) and accumulated during CHM processing. In recent years, increasing attention has been paid to its safety and actions in CHMs, which has led to many reports about different aspects of HMF. In this paper, previous and recent studies on HMF formation, its presence in CHMs, its metabolism and bioactivities, together with its implications for CHMs were summarized, with the purpose of contributing to a better understanding of CHMs

Supplementation with fish oil and genistein, individually or in combination, protects bone against the adverse effects of methotrexate chemotherapy in rats

Cancer chemotherapy has been shown to induce long-term skeletal side effects such as osteoporosis and fractures; however, there are no preventative treatments. This study investigated the damaging effects of anti-metabolite methotrexate (MTX) subcutaneous injections (0.75 mg/kg BW) for five days and the potential protective benefits of daily oral gavage of fish oil at 0.5 mL/100 g BW (containing 375 mg of n-3 PUFA/100 g BW), genistein (2 mg/100 g BW), or their combination in young adult rats. MTX treatment alone significantly reduced primary spongiosa height and secondary spongiosa trabecular bone volume. Bone marrow stromal cells from the treated rats showed a significant reduction in osteogenic differentiation but an increase in adipogenesis ex vivo. Consistently, stromal cells had significantly higher mRNA levels of adipogenesis-related proliferator activator activated receptor-γ (PPAR-γ) and fatty acid binding protein (FABP4). MTX significantly increased the numbers of bone-resorbing osteoclasts and marrow osteoclast precursor cell pool while significantly enhancing the mRNA expression of receptor activator for nuclear factor kappa B ligand (RANKL), the RANKL/osteoprotegerin (OPG) ratio, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in the bone. Supplementary treatment with fish oil and/or genistein significantly preserved trabecular bone volume and osteogenesis but suppressed MTX-induced adipogenesis and increases in osteoclast numbers and pro-osteoclastogenic cytokine expression. Thus, Fish oil and/or genistein supplementation during MTX treatment enabled not only preservation of osteogenic differentiation, osteoblast number and bone volume, but also prevention of MTX treatment-induced increases in bone marrow adiposity, osteoclastogenic cytokine expression and osteoclast formation, and thus bone loss. © 2013 Raghu Nadhanan et al

Potential effects of phytoestrogen genistein in modulating acute methotrexate chemotherapy-induced osteoclastogenesis and bone damage in rats

Chemotherapy-induced bone damage is a frequent side effect which causes diminished bone mineral density and fracture in childhood cancer sufferers and survivors. The intensified use of anti-metabolite methotrexate (MTX) and other cytotoxic drugs has led to the need for a mechanistic understanding of chemotherapy-induced bone loss and for the development of protective treatments. Using a young rat MTX-induced bone loss model, we investigated potential bone protective effects of phytoestrogen genistein. Oral gavages of genistein (20 mg/kg) were administered daily, for seven days before, five days during, and three days after five once-daily injections (sc) of MTX (0.75 mg/kg). MTX treatment reduced body weight gain and tibial metaphyseal trabecular bone volume (p < 0.001), increased osteoclast density on the trabecular bone surface (p < 0.05), and increased the bone marrow adipocyte number in lower metaphyseal bone (p < 0.001). Genistein supplementation preserved body weight gain (p < 0.05) and inhibited ex vivo osteoclast formation of bone marrow cells from MTX-treated rats (p < 0.001). However, MTX-induced changes in bone volume, trabecular architecture, metaphyseal mRNA expression of pro-osteoclastogenic cytokines, and marrow adiposity were not significantly affected by the co-administration of genistein. This study suggests that genistein may suppress MTX-induced osteoclastogenesis; however, further studies are required to examine its potential in protecting against MTX chemotherapy-induced bone damage

A three-dimensional finite element modelling of human chest injury following front or side impact loading

Based on anatomical features of a 50th percentile adult male, three-dimensional (3D) finite element (FE) models of ribs, sternum, vertebrae, intervertebral discs, clavicle, scapula, pelvis, skin, head, muscles and limbs were developed in this study. After integrating/assembling various organs and tissues, a bio-mechanical FE model of the human body with adult male characteristics was produced. Furthermore, a chest frontal and lateral collision theory model was built and was validated by using previously published data from corpse frontal and lateral chest impact collision experiments. Good agreements were found between the simulation results of our model and the experimental data as well as theoretical calculations in the contact force, sternum displacement, and force-displacement response. These data suggest that this 3D FE model is effective and has good bio-fidelity in assessing chest biomechanical responses and thoracic injuries upon impact loading. Therefore this model can potentially be useful for evaluating thoracic injuries in car crashes and assessing chest rib fractures and internal organ/tissue damages

Effects of resveratrol supplementation on methotrexate chemotherapy‐induced bone loss

Intensive cancer chemotherapy is known to cause bone defects, which currently lack treatments. This study investigated the effects of polyphenol resveratrol (RES) in preventing bone defects in rats caused by methotrexate (MTX), a commonly used antimetabolite in childhood oncology. Young rats received five daily MTX injections at 0.75 mg/kg/day. RES was orally gavaged daily for seven days prior to, and during, five‐day MTX administration. MTX reduced growth plate thickness, primary spongiosa height, trabecular bone volume, increased marrow adipocyte density, and increased mRNA expression of the osteogenic, adipogenic, and osteoclastogenic factors in the tibial bone. RES at 10 mg/kg was found not to affect bone health in normal rats, but to aggravate the bone damage in MTX‐treated rats. However, RES supplementation at 1 mg/kg preserved the growth plate, primary spongiosa, bone volume, and lowered the adipocyte density. It maintained expression of genes involved in osteogenesis and decreased expression of adipogenic and osteoclastogenic factors. RES suppressed osteoclast formation ex vivo of bone marrow cells from the treated rats. These data suggest that MTX can enhance osteoclast and adipocyte formation and cause bone loss, and that RES supplementation at 1 mg/kg may potentially prevent these bone defects

A three-dimensional finite element modelling of human chest injury following front or side impact loading

Based on anatomical features of a 50th percentile adult male, three-dimensional (3D) finite element (FE) models of ribs, sternum, vertebrae, intervertebral discs, clavicle, scapula, pelvis, skin, head, muscles and limbs were developed in this study. After integrating/assembling various organs and tissues, a bio-mechanical FE model of the human body with adult male characteristics was produced. Furthermore, a chest frontal and lateral collision theory model was built and was validated by using previously published data from corpse frontal and lateral chest impact collision experiments. Good agreements were found between the simulation results of our model and the experimental data as well as theoretical calculations in the contact force, sternum displacement, and force-displacement response. These data suggest that this 3D FE model is effective and has good bio-fidelity in assessing chest biomechanical responses and thoracic injuries upon impact loading. Therefore this model can potentially be useful for evaluating thoracic injuries in car crashes and assessing chest rib fractures and internal organ/tissue damages