Jeffrey C. Lotz

Bio: Jeffrey C. Lotz is an academic researcher from University of California, San Francisco. The author has contributed to research in topics: Intervertebral disc & Low back pain. The author has an hindex of 74, co-authored 300 publications receiving 15145 citations. Previous affiliations of Jeffrey C. Lotz include University of California & San Francisco General Hospital.

Compression-induced degeneration of the intervertebral disc: an in vivo mouse model and finite-element study.

Abstract: Study design An in vivo study of the biologic and biomechanical consequences of static compressive loading on the mouse tail intervertebral disc. Objectives To determine whether static compression in vivo alters the biologic activity of the disc and leads to diminished biomechanical performance. Summary of background data Static compressive stress that exceeds the disc's swelling pressure is known to change hydration and the intradiscal stress distribution. Alterations in hydration and stress have been associated with changes in disc cell activity in vitro and in other collagenous tissues in vivo. Methods Mouse tail discs were loaded in vivo with an external compression device. After 1 week at one of three different stress levels, the discs were analyzed for their biomechanical performance, morphology, cell activity, and cell viability. A second group of mice were allowed to recuperate for 1 month after the 1-week loading protocol to assess the disc's ability to recover. As an aid to interpreting the histologic and biologic data, finite-element analysis was used to predict region-specific changes in tissue stress caused by the static loading regimen. Results With increasing compressive stress, the inner and middle anulus became progressively more disorganized, and the percentage of cells undergoing apoptosis increased. The expression of Type II collagen was suppressed at all levels of stress, whereas the expression of aggrecan decreased at the highest stress levels in apparent proportion to the decreased nuclear cellularity. Compression for 1 week did not affect the disc bending stiffness or strength but did increase the neutral zone by 33%. As suggested by the finite-element model, during sustained compression, tension is maintained in the outer anulus and lost in the inner and middle regions where the hydrostatic stress was predicted to increased nearly 10-fold. Discs loaded at the lowest stress recovered anular architecture but not cellularity after 1 month of recuperation. Discs loaded at the highest stress did not recover anular architecture, displaying islands of cartilage cells in the middle anulus at sites previously populated by fibroblasts. Conclusions The results of the current project demonstrate that static compressive loading initiates a number of harmful responses in a dose-dependent way: disorganization of the anulus fibrosus; an increase in apoptosis and associated loss of cellularity; and down regulation of collagen II and aggrecan gene expression. The finite element model used in this study predicts loss of collagen fiber tension and increased matrix hydrostatic stress in those anular regions observed to undergo programmed cell death after 1 week of loading and ultimately become populated by chondrocytes after one month of recuperation. This correspondence conforms with the suggestions of others that the cellular phenotype in collagenous tissues is sensitive to the dominant type of tissue stress. Although the specific mechanisms by which alterations in tissue stress lead to apoptosis and variation in cell phenotype remain to be identified, our results suggest that maintenance of appropriate stress within the disc may be an important basis for strategies to mitigate disc degeneration and initiate disc repair.

Intervertebral disc cell therapy for regeneration: mesenchymal stem cell implantation in rat intervertebral discs.

Abstract: This study explores the use of mesenchymal stem cells (MSCs) for intervertebral disc regeneration. We used an in vivo model to investigate the feasibility of exogenous cell delivery, retention, and survival in the pressurized disc space. MSC injection into rat coccygeal discs was performed using 15% hyaluronan gel as a carrier. Injections of gel with or without MSCs were performed. Immediately after injection, fluorescently labeled stem cells were visible on sections of cell-injected discs. Seven and 14 days after injection, stem cells were still present within the disc, but their numbers were significantly decreased. At 28 days, a return to the initial number of injected cells was observed, and viability was 100%. A trend of increased disc height compared to blank gel suggests an increase in matrix synthesis. The results indicate that MSCs can maintain viability and proliferate within the rat intervertebral disc.

Fracture prediction for the proximal femur using finite element models: Part I--Linear analysis.

Abstract: In Part I we reported the results of linear finite element models of the proximal femur generated using geometric and constitutive data collected with quantitative computed tomography. These models demonstrated excellent agreement with in vitro studies when used to predict ultimate failure loads. In Part II, we report our extension of those finite element models to include nonlinear behavior of the trabecular and cortical bone. A highly nonlinear material law, originally designed for representing concrete, was used for trabecular bone, while a bilinear material law was used for cortical bone. We found excellent agreement between the model predictions and in vitro fracture data for both the onset of bone yielding and bone fracture. For bone yielding, the model predictions were within 2 percent for a load which simulated one-legged stance and 1 percent for a load which simulated a fall. For bone fracture, the model predictions were within 1 percent and 17 percent, respectively. The models also demonstrated different fracture mechanisms for the two different loading configurations. For one-legged stance, failure within the primary compressive trabeculae at the subcapital region occurred first, leading to load transfer and, ultimately, failure of the surrounding cortical shell. However, for a fall, failure of the cortical and trabecular bone occurred simultaneously within the intertrochanteric region. These results support our previous findings that the strength of the subcapital region is primarily due to trabecular bone whereas the strength of the intertrochanteric region is primarily due to cortical bone.

Stress distributions within the proximal femur during gait and falls: Implications for osteoporotic fracture

Abstract: The rates of fracture at sites with different relative amounts of cortical and trabecular bone (hip, spine, distal radius) have been used to make inferences about the pathomechanics of bone loss and the existence of type I and type II osteoporosis. However, fracture risk is directly related to the ratio of tissue stress to tissue strength, which in turn is dependent not only on tissue composition but also tissue geometry and the direction and magnitude of loading. These three elements determine how the load is distributed within the tissue. As a result, assumptions on the relative structural importance of cortical and trabecular bone, and how these tissues are affected by bone loss, can be inaccurate if based on regional tissue composition and bone density alone. To investigate the structural significance of cortical and trabecular bone in the proximal femur, and how it is affected by bone loss, we determined the stress distributions in a normal and osteoporotic femur resulting from loadings representing: (1) gait; and (2) a fall to the side with impact onto the greater trochanter. A three-dimensional finite element model was generated based on a representative femur selected from a large database of femoral geometries. Stresses were analyzed throughout the femoral neck and intertrochanteric regions. We found that the percentage of total load supported by cortical and trabecular bone was approximately constant for all load cases but differed depending on location. Cortical bone carried 30% of the load at the subcapital region, 50% at the mid-neck, 96% at the base of the neck and 80% at the intertrochanteric region. These values differ from the widely held assumption that cortical bone carries 75% of the load in the femoral neck and 50% of the load at the intertrochanteric region. During gait, the principal stresses were concentrated within the primary compressive system of trabeculae and in the cortical bone of the intertrochanteric region. In contrast, during a fall, the trabecular stresses were concentrated within the primary tensile system of trabeculae with a peak magnitude 4.3 times that present during gait. While the distribution of stress for the osteoporotic femur was similar to the normal, the magnitude of peak stress was increased by between 33% and 45%. These data call into question several assumptions which serve as the basis for theories on the pathomechanics of osteoporosis. In addition, we expect that the insight provided by this analysis will result in the improved development and interpretation of non-invasive techniques for the quantification of in vivo hip fracture risk.

Intervertebral disc cell death is dependent on the magnitude and duration of spinal loading.

Abstract: Study Design. An in vivo study of the toxic consequences of static compressive stress on the intervertebral disc. Objectives. To determine whether disc cell death is correlated with the magnitude and duration of spinal compressive loading. Summary of Background Data. Static compression in vivo has been demonstrated to induce cell death. Cell death, in turn, has been associated with disc degeneration in humans. There are currently no tolerance criteria for the intervertebral disc that combine both biomechanical and biologic factors, although both have been implicated in cases of accelerated degeneration. Methods. Mouse tail discs were loaded in vivo with an external compression device. Compressive stress was applied at one of two magnitudes (0.4 and 0.8 MPa) for 7 days, and at one additional magnitude (1.3 MPa) for 1, 3, and 7 days. Midsagittal sections of the discs were stained for apoptosis using the TdT-dUTP terminal nick-end labeling (TUNEL) reaction. Quantal analysis was used to correlate the extent of cell death to the magnitude and duration of loading. Results: The probit transformation of the percentage of dying cells was proportional to the sum of the logarithmic transformations of the compressive stress and the time of loading. Conclusions. The results of this study demonstrate the feasibility of developing a quantitative correlation between spinal loading and disc degeneration. Such a correlation may be coupled in the future to existing engineering models that predict spinal loading in response to physical exposures and lead to improved definition of the bounds of healthy and unhealthy spinal loading, and ultimately, refined guidelines for low back safety.

How Matrix Metalloproteinases Regulate Cell Behavior

Abstract: ▪ Abstract The matrix metalloproteinases (MMPs) constitute a multigene family of over 25 secreted and cell surface enzymes that process or degrade numerous pericellular substrates. Their targets include other proteinases, proteinase inhibitors, clotting factors, chemotactic molecules, latent growth factors, growth factor–binding proteins, cell surface receptors, cell-cell adhesion molecules, and virtually all structural extracellular matrix proteins. Thus MMPs are able to regulate many biologic processes and are closely regulated themselves. We review recent advances that help to explain how MMPs work, how they are controlled, and how they influence biologic behavior. These advances shed light on how the structure and function of the MMPs are related and on how their transcription, secretion, activation, inhibition, localization, and clearance are controlled. MMPs participate in numerous normal and abnormal processes, and there are new insights into the key substrates and mechanisms responsible for regula...

Mesenchymal Stem Cells Derived from Dental Tissues vs. Those from Other Sources: Their Biology and Role in Regenerative Medicine

Abstract: To date, 5 different human dental stem/progenitor cells have been isolated and characterized: dental pulp stem cells (DPSCs), stem cells from exfoliated deciduous teeth (SHED), periodontal ligament stem cells (PDLSCs), stem cells from apical papilla (SCAP), and dental follicle progenitor cells (DFPCs). These post-natal populations have mesenchymal-stem-cell-like (MSC) qualities, including the capacity for self-renewal and multilineage differentiation potential. MSCs derived from bone marrow (BMMSCs) are capable of giving rise to various lineages of cells, such as osteogenic, chondrogenic, adipogenic, myogenic, and neurogenic cells. The dental-tissue-derived stem cells are isolated from specialized tissue with potent capacities to differentiate into odontogenic cells. However, they also have the ability to give rise to other cell lineages similar to, but different in potency from, that of BMMSCs. This article will review the isolation and characterization of the properties of different dental MSC-like populations in comparison with those of other MSCs, such as BMMSCs. Important issues in stem cell biology, such as stem cell niche, homing, and immunoregulation, will also be discussed.