Muscle secreted factors enhance activation of the PI3K/Akt and ß-catenin pathways in murine osteocytes.

Skeletal muscle and bone interact at the level of mechanical loading through the application of force by muscles to the skeleton and more recently focus has been placed on molecular/biochemical coupling of these two tissues. We sought to determine if muscle and muscle-derived factors were essential to the osteocyte response to loading. Botox® induced muscle paralysis was used to investigate the role of muscle contraction during in vivo tibia compression loading. 5-6 month-old female TOPGAL mice had their right hindlimb muscles surrounding the tibia injected with either BOTOX® or saline. At four days post injections when muscle paralysis peaked, the right tibia was subjected to a single session of in vivo compression loading at ∼2600 µÎµ. At 24 h post-load we observed a 2.5-fold increase in ß-catenin signaling in osteocytes in the tibias of the saline injected mice, whereas loading of tibias from Botox® injected mice failed to active ß-catenin signaling in osteocytes. This suggests that active muscle contraction produces a factor(s) that is necessary for or conditions the osteocyte's ability to respond to load. To further investigate the role of muscle derived factors, MLO-Y4 osteocyte-like cells and a luciferase based ß-catenin reporter (TOPflash-MLO-Y4) cell line we developed were treated with conditioned media (CM) from C2C12 myoblasts (MB) and myotubes (MT) and ex vivo contracted Extensor Digitorum Longus (EDL) and Soleus (Sol) muscles under static or loading conditions using fluid flow shear stress (FFSS). 10 % C2C12 myotube CM, but not myoblast or NIH3T3 fibroblast cells CM, induced a rapid activation of the Akt signaling pathway, peaking at 15 min and returning to baseline by 1-2 h under static conditions. FFSS applied to MLO-Y4 cells for 2 h in the presence of 10 % MT-CM resulted in a 6-8 fold increase in pAkt compared to a 3-4 fold increase under control or when exposed to 10 % MB-CM. A similar response was observed in the presence of 10 % EDL-CM, but not in the presence of 10 % Sol-CM. TOPflash-MLO-Y4 cells were treated with 10 ng/ml Wnt3a in the presence or absence of MT-CM. While MT-CM resulted in a 2-fold activation and Wnt3a produced a 10-fold activation, the combination of MT-CM + Wnt3a resulted in a 25-fold activation of ß-catenin signaling, implying a synergistic effect of factors in MT-CM with Wnt3a. These data provide clear evidence that specific muscles and myotubes produce factors that alter important signaling pathways involved in the response of osteocytes to mechanical load. These data strongly suggest that beyond mechanical loading there is a molecular coupling of muscle and bone.

Trimalleolar fracture and associated Achilles tendon rupture: Ten year follow up of an unusual water-skiing injury.

A 49 year old professional fitness instructor sustained a high velocity rotational injury to his right ankle while waterski-ing. The ski bindings did not release, exacerbating the injury. This resulted in a trimalleolar fracture and a rupture of his Achilles tendon. A trimalleolar fracture in association with a rupture of the Achilles tendon has not been previously reported. This combination of injuries posed a dilemma in treatment options and postoperative management. The authors felt that ensuring that the Achilles tendon healed with no shortening was the priority for future function in this professional athlete. It was decided to treat the Achilles tendon rupture by open repair and to place the ankle in equinus postoperatively. It was also decided to openly reduce and internally fix the medial and lateral malleolar fractures before immobilising the ankle in equinus. Any residual stiffness in the ankle, subtalar and midtarsal joints would be treated with aggressive physiotherapy. It was felt that the rotational forces may have resulted in a degree of degloving around the ankle. Care was therefore taken in the choice and placement of the surgical incisions. In spite of this, the lateral surgical wound broke down postoperatively, needing treatment with a fasciocutaneous flap. When reviewed at ten years following the injury, the patient was continuing to work as a fitness instructor with a view to continuing to retirement in five years at the age of 65. There was a slight decrease in dorsiflexion of the right ankle but flexion was full and movement of the subtalar and midtarsal joints were also full. There remained 1 cm of wasting of the right calf. Radiology of the ankle showed no joint space narrowing or evidence of degenerative change at ten years following the injury.

Numerical simulation of peristaltic flow of a biorheological fluid with shear-dependent viscosity in a curved channel.

Peristaltic motion of a non-Newtonian Carreau fluid is analyzed in a curved channel under the long wavelength and low Reynolds number assumptions, as a simulation of digestive transport. The flow regime is shown to be governed by a dimensionless fourth-order, nonlinear, ordinary differential equation subject to no-slip wall boundary conditions. A well-tested finite difference method based on an iterative scheme is employed for the solution of the boundary value problem. The important phenomena of pumping and trapping associated with the peristaltic motion are investigated for various values of rheological parameters of Carreau fluid and curvature of the channel. An increase in Weissenberg number is found to generate a small eddy in the vicinity of the lower wall of the channel, which is enhanced with further increase in Weissenberg number. For shear-thinning bio-fluids (power-law rheological index, n < 1) greater Weissenberg number displaces the maximum velocity toward the upper wall. For shear-thickening bio-fluids, the velocity amplitude is enhanced markedly with increasing Weissenberg number.

Implementation of and compliance with NICE guidelines in the secondary prevention of osteoporotic fractures in postmenopausal women.

Osteoporosis affects more than 1.2 million women in England and Wales. Hip fractures are associated with increased mortality. The total cost of treating osteoporotic fractures in postmenopausal women is expected to rise to pound 2.1 billion by 2010. The National Institute for Health and Clinical Excellence (NICE) has issued guidelines for the secondary prevention of osteoporotic fractures in postmenopausal women. The objective of this study was to review the NICE guidelines and to assess the implementation of and compliance with these guidelines in a district general hospital.