Abstract-If musculoskeletal tissues are indeed efficient for their mechanical function, it is most reasonable to assume that this is achieved because the mechanical environment in the tissue influences cell differentiation and expression. Although mechanical stimuli can influence the transport of bio active factors, cell deformation and cytoskeletal strain, the question of whether or not they have the potential to regulate tissue differentiation sequences (for example, during fracture healing or embryogenesis) has not been answered.To assess the feasibility of biophysical stimuli as mediators of tissue differentiation, we analysed intcrfacial tissue formation adjacent to a micromotion device implanted into the condyles of dogs, A biphasic finite element model was used and the mechanical environment in the tissue was characterised in terms of (i) forces opposing implant motion, (ii) relative velocity between constituents, (iii) fluid pressure, (iv) deformation of the tissue and (v) strain in the tissue. It was predicted that, as tissue differentiation progressed, subtle but systematic mechanical changes occur on cells in the interfacial tissue. Specifically, as the forces opposing motion increase, the implant changes from being controlled by the maximum-allowable displacement (motion-control) to being controlled by the maximum-available load (force-control). This causes a decrease in the velocity of the fluid phase relative to the solid phase and a drop in interstitial fluid pressure accompanied by a reduction in peri-prosthetic tissue strains. The variation of biophysical stimuli within the tissue can be plotted as 'mechano-regulatory pathway', which identifies the transition from motion-control to force-control as a branching event in the tissue differentiation sequence. © 1997 Elsevier Science Ltd

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Mechanical forces are essential for normal adult bone function and repair, but the impact of prenatal muscle contractions on bone development remains to be explored in depth in mammalian model systems. In this study, we analyze skeletogenesis in two ‘muscleless’ mouse mutant models in which the formation of skeletal muscle development is disrupted; Myf5nlacZ/nlacZ:MyoD−/− and Pax3Sp/Sp (Splotch). Ossification centers were found to be differentially affected in the muscleless limbs, with significant decreases in bone formation in the scapula, humerus, ulna and femur, but not in the tibia. In the scapula and humerus, the morphologies of ossification centers were abnormal in muscleless limbs. Histology of the humerus revealed a decreased extent of the hypertrophic zone in mutant limbs but no change in the shape of this region. The elbow joint was also found to be clearly affected with a dramatic reduction in the joint line, while no abnormalities were evident in the knee. The humeral deltoid tuberosity was significantly reduced in size in the Myf5nlacZ/nlacZ:MyoD−/− mutants while a change in shape but not in size was found in the humeral tuberosities of the Pax3Sp/Sp mutants. We also examined skeletal development in a ‘reduced muscle’ model, the Myf5nlacZ/+:MyoD−/− mutant, in which skeletal muscle forms but with reduced muscle mass. The reduced muscle phenotype appeared to have an intermediate effect on skeletal development, with reduced bone formation in the scapula and humerus compared to controls, but not in other rudiments. In summary, we have demonstrated that skeletal development is differentially affected by the lack of skeletal muscle, with certain rudiments and joints being more severely affected than others. These findings indicate that the response of skeletal progenitor cells to biophysical stimuli may depend upon their location in the embryonic limb, implying a complex interaction between mechanical forces and location-specific regulatory factors affecting bone and joint development.