Nina Hamann

Effect of different running modes on the morphological, biochemical, and mechanical properties of articular cartilage.

Mechanical loading plays an important role not solely in cartilage development, but also in cartilage degeneration. Its adaptation behavior to mechanical loading has not been clearly delineated. The aim of the study was to examine the effect of different running modes (with different muscle contraction types) on morphological, biochemical, and mechanical properties of articular cartilage in the knee of growing rats. Thirty‐six female Sprague–Dawley rats were randomly assigned into a nonactive age‐matched control (AMC), level (LEVEL), and 20° downhill (DOWN) running group (n = 12 each). Running groups were trained on a treadmill for 30 min/day, 5 days/week for 6 weeks. Immunohistochemical staining and analysis of expression for collagen II, collagen IX, cartilage oligomeric matrix protein (COMP), and matrilin‐3, histomorphometry of femoral cartilage height and femoral COMP staining height, and indentation testing of tibial articular cartilage were performed. Rats subjected to downhill running showed a significantly (P = 0.015) higher COMP staining height and a tendentially (P = 0.084) higher cartilage height in the high‐weight bearing area of femoral articular cartilage. Cartilage thickness, mechanical properties, and expression of cartilage network proteins in tibial cartilage remained unaffected by different running modes. Our data suggest that joint loading induced by eccentric muscle contractions during downhill running may lead to a site‐specific adaptation.

Doxycycline‐Induced Expression of Transgenic Human Tumor Necrosis Factor α in Adult Mice Results in Psoriasis‐like Arthritis

Objective To generate doxycycline-inducible human tumor necrosis factor α (TNFα)–transgenic mice to overcome a major disadvantage of existing transgenic mice with constitutive expression of TNFα, which is the limitation in crossing them with various knockout or transgenic mice. Methods A transgenic mouse line that expresses the human TNFα cytokine exclusively after doxycycline administration was generated and analyzed for the onset of diseases. Results Doxycycline-inducible human TNFα–transgenic mice developed an inflammatory arthritis– and psoriasis-like phenotype, with fore and hind paws being prominently affected. The formation of “sausage digits” with characteristic involvement of the distal interphalangeal joints and nail malformation was observed. Synovial hyperplasia, enthesitis, cartilage and bone alterations, formation of pannus tissue, and inflammation of the skin epidermis and nail matrix appeared as early as 1 week after the treatment of mice with doxycycline and became aggravated over time. The abrogation of human TNFα expression by the removal of doxycycline 6 weeks after beginning stimulation resulted in fast resolution of the most advanced macroscopic and histologic disorders, and 3–6 weeks later, only minimal signs of disease were visible. Conclusion Upon doxycycline administration, the doxycycline-inducible human TNFα–transgenic mouse displays the major features of inflammatory arthritis. It represents a unique animal model for studying the molecular mechanisms of arthritis, especially the early phases of disease genesis and tissue remodeling steps upon abrogation of TNFα expression. Furthermore, unlimited crossing of doxycycline-inducible human TNFα–transgenic mice with various knockout or transgenic mice opens new possibilities for unraveling the role of various signaling molecules acting in concert with TNFα.

Stabilization effectiveness and functionality of different thumb orthoses in female patients with first carpometacarpal joint osteoarthritis.

BACKGROUND Thumb orthoses have to reconcile and satisfy competing goals: stability and mobility. The purpose of the study was to characterize the stabilization effectiveness and functionality of different thumb carpometacarpal osteoarthritis orthoses. METHODS Eighteen female carpometacarpal osteoarthritis subjects were included. Four orthoses were compared: BSN medical (BSN); Push braces (PUSH); Sporlastic (SPOR); and medi (MEDI). Three-dimensional thumb kinematics during active opposition-reposition with and without orthosis was quantified. Ranges-of-motion of the carpometacarpal and metacarpophalangeal joint in x- (flexion-extension), y- (adduction-abduction) and z-direction (pronation-supination) were determined. Hand functionality was examined by Sollerman test. FINDINGS All orthoses restricted carpometacarpal range-of-motion in all directions. In x-direction carpometacarpal range-of-motion was smallest with MEDI and BSN, in y-direction largest with PUSH compared to all other orthoses, in z-direction smaller with BSN and MEDI compared to PUSH, but similar to SPOR. All orthoses restricted metacarpophalangeal range-of-motion in x-direction, except PUSH. In x-direction metacarpophalangeal range-of-motion was smallest with MEDI compared to all other orthoses. In y-direction and z-direction only BSN and MEDI restricted metacarpophalangeal range-of-motion. Sollerman score was highest with PUSH, lowest with MEDI and both differed from other orthoses. Values for BSN and SPOR were similar and lay between PUSH and MEDI. INTERPRETATION Stabilization is borne by functionality. The high stabilization effectiveness provided by MEDI resulted in lowest hand functionality. PUSH, which partially stabilized the CMC joint and allowed large motions in the MCP joint, afforded largest hand functionality. Best compromise of stability and functionality could be reached with BSN. Long-term studies are needed to monitor clinical efficacy.

Growth-related structural, biochemical, and mechanical properties of the functional bone-cartilage unit.

Articular cartilage and subchondral bone act together, forming a unit as a weight‐bearing loading‐transmitting surface. A close interaction between both structures has been implicated during joint cartilage degeneration, but their coupling during normal growth and development is insufficiently understood. The purpose of the present study was to examine growth‐related changes of cartilage mechanical properties and to relate these changes to alterations in cartilage biochemical composition and subchondral bone structure. Tibiae and femora of both hindlimbs from 7‐ and 13‐week‐old (each n = 12) female Sprague‐Dawley rats were harvested. Samples were processed for structural, biochemical and mechanical analyses. Immunohistochemical staining and protein expression analyses of collagen II, collagen IX, COMP and matrilin‐3, histomorphometry of cartilage thickness and COMP staining height were performed. Furthermore, mechanical testing of articular cartilage and micro‐CT analysis of subchondral bone was conducted. Growth decreased cartilage thickness, paralleled by a functional condensation of the underlying subchondral bone due to enchondral ossification. Cartilage mechanical properties seem to be rather influenced by growth‐related changes in the assembly of major ECM proteins such as collagen II, collagen IX and matrilin‐3 than by growth‐related alterations in its underlying subchondral bone structure. Importantly, the present study provides a first insight into the growth‐related structural, biochemical and mechanical interaction of articular cartilage and subchondral bone. Finally, these data contribute to the general knowledge about the cooperation between the articular cartilage and subchondral bone.

Moderate Cyclic Tensile Strain Alters the Assembly of Cartilage Extracellular Matrix Proteins In Vitro

Mechanical loading influences the structural and mechanical properties of articular cartilage. The cartilage matrix protein collagen II essentially determines the tensile properties of the tissue and is adapted in response to loading. The collagen II network is stabilized by the collagen II-binding cartilage oligomeric matrix protein (COMP), collagen IX, and matrilin-3. However, the effect of mechanical loading on these extracellular matrix proteins is not yet understood. Therefore, the aim of this study was to investigate if and how chondrocytes assemble the extracellular matrix proteins collagen II, COMP, collagen IX, and matrilin-3 in response to mechanical loading. Primary murine chondrocytes were applied to cyclic tensile strain (6%, 0.5 Hz, 30 min per day at three consecutive days). The localization of collagen II, COMP, collagen IX, and matrilin-3 in loaded and unloaded cells was determined by immunofluorescence staining. The messenger ribo nucleic acid (mRNA) expression levels and synthesis of the proteins were analyzed using reverse transcription-polymerase chain reaction (RT-PCR) and western blots. Immunofluorescence staining demonstrated that the pattern of collagen II distribution was altered by loading. In loaded chondrocytes, collagen II containing fibrils appeared thicker and strongly co-stained for COMP and collagen IX, whereas the collagen network from unloaded cells was more diffuse and showed minor costaining. Further, the applied load led to a higher amount of COMP in the matrix, determined by western blot analysis. Our results show that moderate cyclic tensile strain altered the assembly of the extracellular collagen network. However, changes in protein amount were only observed for COMP, but not for collagen II, collagen IX, or matrilin-3. The data suggest that the adaptation to mechanical loading is not always the result of changes in RNA and/or protein expression but might also be the result of changes in matrix assembly and structure.

Topographical variations in articular cartilage and subchondral bone of the normal rat knee are age-related.

In osteoarthritis animal models the rat knee is one of the most frequently investigated joint. However, it is unknown whether topographical variations in articular cartilage and subchondral bone of the normal rat knee exist and how they are linked or influenced by growth and maturation. Detailed knowledge is needed in order to allow interpretation and facilitate comparability of published osteoarthritis studies. For the first time, the present study maps topographical variations in cartilage thickness, cartilage compressive properties and subchondral bone microarchitecture between the medial and lateral tibial compartment of normal growing rat knees (7 vs. 13 weeks). Thickness and compressive properties (aggregate modulus) of cartilage were determined and the subchondral bone was analyzed by micro-computed tomography. We found that articular cartilage thickness is initially homogenous in both compartments, but then differentiates during growth and maturation resulting in greater cartilage thickness in the medial compartment in the 13-week-old animals. Cartilage compressive properties did not vary between the two sites independently of age. In both age-groups, subchondral plate thickness as well as trabecular bone volume ratio and trabecular thickness were greater in the medial compartment. While a high porosity of subchondral bone plate with a high topographical variation (medial/lateral) could be observed in the 7-week-old animals, the porosity was reduced and was accompanied by a reversion in topographical variation when reaching maturity. Our findings highlight that there is a considerable topographical variation in articular cartilage and subchondral bone within the normal rat knee in relation to the developmental status.

Biomimetic Design of Lightweight Vehicle Structures Based on Animal Bone Properties

This paper presents a comprehensive biomimetic design approach to developing novel load bearing lightweight vehicle structures inspired by the structural properties of animal bones. Lightweight vehicle structures developed in this way would have increased stiffness at significantly reduced weight. In this research, trabecular (cancellous) bone was analyzed at the metaphyses of four different species including rat, rabbit, chicken, and sheep. Three-dimensional models of bone structures were reconstructed from micro-CT scanned images using the computer aided design software Mimics. Force resistance and energy absorption properties of relevant bone structures subjected to quasi-static compression loads were investigated and analysed using the Finite Element (FE) method. Based on the obtained results, the paper discusses the effects of load directions, bone structure allocation and model thickness on the energy absorption and force resistance of the bone structures. The simulation results obtained in this research were compared to the results of conventional vehicle side intrusion bars.

THE INFLUENCE OF WHOLE-BODY VIBRATION AND IGF-I ON MUSCLE PARALYSIS-INDUCED BONE DEGRADATION

Mechanical loading through muscle contraction is essential for bone homeostasis and maintenance. Consequently, muscle paralysis induced by Botulinum neurotoxin (Botox) results in bone degradation [Warner, 2006]. On the other hand, it is well known that high-frequency mechanical loading has an anabolic effect on bone (Rubin et al. 2004) and that insulin growth factor I (IGF-I) is essential for bone growth and formation [Baker, 1993]. Interestingly, it has been shown that skeletal unloading leads to a resistance to IGF-I [Bikle, 1994, Sakata, 2004]. The purpose of the present study was to analyze if whole body vibration (WBV) and IGF-I can counteract muscle paralysisinduced bone degradation.

DISTRIBUTION OF COMP IN HUMAN HEALTHY AND OSTEOARTHRITIC CARTILAGE

The mechanical properties of the articular cartilage depend on the composition of the extracellular matrix (ECM). Collagen II is the most abundant protein in articular cartilage and it is assembled in heterotypic collagen fibrils forming a suprastructural network. Cartilage oligomeric matrix protein (COMP) binds to collagen II and acts as a catalyst in collagen fibrillogenesis [Halasz, 2007]. Furthermore, COMP is an established biomarker for OA [Petersson, 1998] and COMP levels are increased in the serum after physical activity [Niehoff, 2011]. The mechanosensitivity of COMP is also reflected by an elevated synthesis in response to mechanical loading [Giannoni, 2003]. In OA, the cartilage shows critical alterations in structure and composition of the ECM. However, many OA studies are based on animal models. Therefore, the aim of the study was to analyse the localization and distribution of both collagen II and COMP in human OA and healthy cartilage.

DOWNHILL RUNNING INDUCES SITE-SPECIFIC ARTICULAR CARTILAGE ALTERATIONS

The mechanical performance of articular cartilage and its optimization for load-bearing function is determined by the biochemical assembly of the extracellular matrix (ECM) [Mow, 1992]. Both magnitude and type of mechanical loading have the potential to alter ECM protein synthesis of collagen II and cartilage oligomeric matrix protein (COMP), two major network stabilizing proteins, in a sitespecific manner [Kiviranta, 1988, Skioldebrand, 2010]. Downhill running as a natural form of eccentric exercise [Butterfield, 2005] has been shown to induce higher knee joint loadings compared to level running [Kuster, 1995]. However, its influence on articular cartilage assembly and mechanical properties has not yet been studied. In the present study we examined the effect of different running modes (downhill vs. level) on site-specific cartilage adaptation.