Biomedical subjects

Jeffry S Nyman

Publications and source records attributed to Jeffry S Nyman.

8 recordsLinked to original sources

PubMed2011

Mice lacking Nf1 in osteochondroprogenitor cells display skeletal dysplasia similar to patients with neurofibromatosis type I.

Mutations in NF1 cause neurofibromatosis type I (NF1), a disorder characterized, among other clinical manifestations, by generalized and focal bony lesions. Dystrophic scoliosis and tibial pseudoarthrosis are the most severe skeletal manifestations for which treatment is not satisfactory, emphasizing the dearth of knowledge related to the biology of NF1 in bone cells. Using reporter mice, we report here that the mouse Col2α1-Cre promoter (collagen, type II, alpha 1) is active not only in chondrocytes but also in adult bone marrow osteoprogenitors giving rise to osteoblasts. Based on this finding, we crossed the Col2α1-Cre transgenic and Nf1(flox/flox) mice to determine whether loss of Nf1 in axial and appendicular osteochondroprogenitors recapitulates the skeletal abnormalities of NF1 patients. By microtomographic and X-rays studies, we show that Nf1(Col2)(-/-) mice display progressive scoliosis and kyphosis, tibial bowing and abnormalities in skull and anterior chest wall formation. These defects were accompanied by a low bone mass phenotype, high bone cortical porosity, osteoidosis, increased osteoclastogenesis and decreased osteoblast number, as quantified by histomorphometry and 3D-microtomography. Loss of Nf1 in osteochondroprogenitors also caused severe short stature and intervertebral disc defects. Blockade of the RAS/ERK activation characteristic of Nf1(-/-) osteoprogenitors by lovastatin during embryonic development could attenuate the increased cortical porosity observed in mutant pups. These data and the skeletal similarities between this mouse model and NF1 patients thus suggest that activation of the RAS/ERK pathway by Nf1 loss-of-function in osteochondroprogenitors is responsible for the vertebral and tibia lesions in NF1 patients, and that this molecular signature may represent a good therapeutic target.

Animals↗

PubMed2007

A novel approach to assess post-yield energy dissipation of bone in tension.

In this study, we proposed a novel approach to assess the energy dissipation during the post-yield deformation of bone. Based on the stress-strain behavior in an incremental and cyclic loading-unloading-reloading scheme in uniaxial tension, we partitioned the post-yield energy dissipation of bone into three distinct pathways: released elastic strain energy (U(er)); irreversible energy (U(i)); and hysteresis energy (U(h)). Among them, U(er) depends on the stiffness loss, U(i) is the energy permanently consumed, and U(h) reflects changes in the viscoelastic behavior of bone in the process of post-yield deformation. As an example, bone specimens from human cadaveric femurs of middle-aged and elderly donors were tested using this approach. The results of this study indicate that there exist age-related differences in post-yield energy dissipation and modulus degradation. These results implicate that this novel approach could detect the age-related differences in energy dissipation of bone and may aid in understanding the underlying mechanisms of such changes.

Aged↗

PubMed2006

Age-related effect on the concentration of collagen crosslinks in human osteonal and interstitial bone tissue.

Collagen crosslinks are important to the quality of bone and may be contributors to the age-related increase in bone fracture. This study was performed to investigate whether age and gender effects on collagen crosslinks are similar in osteonal and interstitial bone tissues. Forty human cadaveric femurs were collected and divided into two age groups: middle-aged (42-63 years of age) and elderly (69-90 years of age) with ten males and ten females in each group (n = 10). Micro-cores of bone tissue from both secondary osteons and interstitial regions in the medial quadrant of the diaphysis were extracted using a custom-modified, computer-controlled milling machine. The bone specimens were then analyzed using high performance liquid chromatography to determine the effects of age and gender on the concentration of mature, enzymatic crosslinks (hydroxylysyl-pyridinoline-HP and lysyl-pyridinoline-LP) and a non-enzymatic crosslink (pentosidine-PE) at these two microstructural sites. The results indicate that age has a significant effect on the concentration of LP and PE, while gender has a significant effect on HP and LP. In addition, the concentration of the crosslinks in the secondary osteons is significantly different from that in the interstitial bone regions. These results suggest that the amount of non-enzymatic crosslinking may increase while that of mature enzymatic crosslinking may decrease with age. Such changes could potentially reduce the inherent quality of the bone tissue in the elderly skeleton.

Adult↗

PubMed2006

Predictions on preserving bone mass in knee arthroplasty with bisphosphonates.

Using a computational model of bone adaptation, we investigated the long-term ability of bisphosphonates to minimize proximal bone loss that is associated with stress shielding in the tibia after long-stemmed total knee arthroplasty (TKA). When invoking bisphosphonate effects, the remodeling activity was suppressed, and the resorption size was reduced. Compared with the untreated simulation, bisphosphonate slowed the rate of bone loss after TKA (42% reduction in bone loss at 1 year). Activating the drug 3 months before the surgery reversed bone loss associated with the reduction in such activities as walking, but it did not provide any substantial benefit in the long-term. Late bisphosphonate treatment did not reverse the bone loss that occurred 3.5 years after TKA, although it preserved 3% of bone normally lost without treatment.

Arthroplasty, Replacement, Knee↗

PubMed2006

The influence of water removal on the strength and toughness of cortical bone.

Although the effects of dehydration on the mechanical behavior of cortical bone are known, the underlying mechanisms for such effects are not clear. We hypothesize that the interactions of water with the collagen and mineral phases each have a unique influence on mechanical behavior. To study this, strength, toughness, and stiffness were measured with three-point bend specimens made from the mid-diaphysis of human cadaveric femurs and divided into six test groups: control (hydrated), drying in a vacuum oven at room temperature (21 degrees C) for 30 min and at 21, 50, 70, or 110 degrees C for 4 h. The experimental data indicated that water loss significantly increased with each increase in drying condition. Bone strength increased with a 5% loss of water by weight, which was caused by drying at 21 degrees C for 4 h. With water loss exceeding 9%, caused by higher drying temperatures (> or =70 degrees C), strength actually decreased. Drying at 21 degrees C (irrespective of time in vacuum) significantly decreased bone toughness through a loss of plasticity. However, drying at 70 degrees C and above caused toughness to decrease through decreases in strength and fracture strain. Stiffness linearly increased with an increase in water loss. From an energy perspective, the water-mineral interaction is removed at higher temperatures than the water-collagen interaction. Therefore, we speculate that loss of water in the collagen phase decreases the toughness of bone, whereas loss of water associated with the mineral phase decreases both bone strength and toughness.

Adult↗

PubMed2005

Effect of ultrastructural changes on the toughness of bone.

The ultrastructure of bone can be considered as a conjunction between the biology and the biomechanics of the tissue. It is the result of cellular and molecular activities of bone formation, and its organization dominates the mechanical behavior of bone. Following this perspective, the objective of this review is to provide a current understanding of bone ultrastructure and its relationships with the toughness of the tissue. Therefore, we first provide a discussion on the organization of bone constituents, namely collagen, mineral, and water. Then, we present evidence on how the toughness of bone relates to its ultrastructure through the formation of micro damage. In addition, attention is given to how damage accumulation serves as a toughening mechanism. Finally, we describe how changes in the ultrastructure-caused by osteogenesis imperfecta, gamma irradiation, fluoride treatment, and aging affect the toughness and competence of bone.

Aging↗

PubMed2004

A theoretical analysis of long-term bisphosphonate effects on trabecular bone volume and microdamage.

Bisphosphonates increase bone mass and reduce fracture risk, but their anti-resorptive action may lead to increases in fatigue microdamage. To investigate how bisphosphonate effects influence changes in bone volume and microdamage in the long term, a strain-adaptive model of bone remodeling and microdamage balance was developed for a continuum-level volume of postmenopausal trabecular bone by invoking Frost's mechanostat hypothesis. Both disuse and fatigue microdamage were assumed to stimulate the activation frequency of basic multicellular units (BMUs) such that bone remodeling served to remove excess bone mass and microdamage. Bisphosphonate effects were simulated as follows: low, intermediate, high, or complete suppression of BMU activation frequency either without a change in resorption by the BMU or with an independent decrease in resorption while the bone formation process was unaffected (i.e., formation initially exceeded resorption). Of the bisphosphonate effects, a reduction in resorption relative to formation dictated the long-term gain in bone volume while the potency of activation frequency suppression controlled the rate of gain. A plateau in the bone mass gain that typically occurs in clinical studies of bisphosphonate treatment was predicted by the model because the resultant reduction in strain forced bone formation by the BMU to decrease over time until it matched the reduction in BMU resorption. A greater suppression of activation frequency proportionally increased microdamage, but the accumulation was limited over the long term as long as remodeling was incompletely suppressed. The results of the model suggest creating bisphosphonates that provide minimal suppression of remodeling and a large decrease in BMU resorption because this would minimize damage accumulation and increase bone mass, respectively.

Biomechanical Phenomena↗

PubMed2004

Long stemmed total knee arthroplasty with interlocking screws: a computational bone adaptation study.

The ability of an interlocking screw fixation technique to minimize bone loss related to stress shielding in the tibia was investigated and compared to the abilities of cement and press-fit fixation. Full bony ingrowth has been associated with greater stress shielding than partial ingrowth; therefore, the effect of intimate bonding of the stem to bone on subsequent bone loss was also studied. A damage- and disuse-based remodeling theory was coupled with a two-dimensional finite element model of the tibia to predict changes in bone remodeling following long stemmed total knee arthroplasty (TKA) for four different fixation techniques (cement, press-fit, interlock with bony ingrowth, and interlock without bony ingrowth). Remodeling changes commenced with the model state variables--bone area fraction, mechanical stimulus, damage, and remodeling activity--at steady-state values predicted by the intact tibia simulation. After TKA and irrespective of fixation technique, the model predicted elevated remodeling due to disuse, in which more bone was removed than replenished. In regions below the tibial tray and along the cortices, the interlocking stem with full bony ingrowth and the cemented stem caused the least amount of bone loss. An interlocking stem with a smooth, matted finish did not reduce the bone loss associated with interlocking fixation.

Adaptation, Physiological↗