Mechanical loading is essential for bone development and prevention of age-related bone diseases. Muscular contractions during physical activity and the generated strain magnitude are primary determinants for the osteogenic response. However, the adaptation capacity of bones, especially due to different muscle contraction types, is largely unknown. In the present study we examined the effect of different running modes characterized by different muscle contraction types and loading patterns on the morphological, structural, and mechanical properties of different sites in the femur of growing rats. Thirty-six female Sprague-Dawley rats were randomly assigned to a nonactive age-matched control (AMC), a level running (LEVEL), and a 20° decline downhill running (DOWN) group (n = 12 each). Running groups were trained on a treadmill for 30 min/day, 5 days/week for 6 weeks. After death, pQCT analysis of the meta- and diaphyses, micro-CT analysis of the epiphysis, and mechanical testing of the femur were performed. The Tb.BMD in the metaphysis was significantly (P < 0.05) increased in the DOWN compared to the AMC group, whereas level running had no effect on Tb.BMD. While Young's modulus was significantly different (P < 0.05) between the DOWN and LEVEL groups, no structural alterations were found in the diaphysis between the groups. Further, subchondral trabecular bone did not show exercise-induced changes caused by the different running modes but displayed a remarkably high intraepiphyseal variability. Downhill running seems to be a potent osteogenic stimulus in the femoral metaphysis.

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ObjectiveTo 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.MethodsA transgenic mouse line that expresses the human TNFα cytokine exclusively after doxycycline administration was generated and analyzed for the onset of diseases.ResultsDoxycycline-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.ConclusionUpon 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.

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.