Role of Mechanical Force on the Growth Plate

Abstract

The shape and size of the limb is determined by genetic, biochemical, and mechanical factors resulting from weight bearing activity or muscle contraction. Changes in bone shape in response to mechanical forces was first reported by Wolf, 1892. Observations by Hueter‐Volkman indicated that supraphysiological forces lead to reduced skeletal growth. More recently, Frost (1990) proposed the concept of chondral modeling to describe physiological loading. In this case, both tension and compression lead to increased skeletal growth up to a peak then compression beyond that peak leads to inhibition of growth. Recent experiments using zebra fish, chick, and muscle‐less Spd mice indicated a specific connection between mechanical load and endochondral bone formation in embryonic skeleton. A role for mechanical forces on postnatal skeletal development is apparent in clinical manifestations of children with hemiplegia resulting in unequal loading of developing limbs. A large proportion of children with hemiplegia demonstrated significant limb length discrepancy with the paralyzed limb being shorter than the other limb. An age dependent effect of force on limb development in mice during spaceflight and tail suspended rats indicated a critical developmental window where loading regulates growth plate function. Longitudinal growth of limbs occurs through cartilaginous structures called the growth plate in a process called endochondral bone formation. One important feature of the growth plate is that the cells align into columns that represent a continuum of differentiation. It was suggested that the magnitude of bone growth is dependent on chondrocyte proliferation, matrix deposition, and hypertrophy; however, without the columnar structure, growth would not be longitudinal and the proper length and shape of skeletal elements would be disrupted. Recent experimental data indicate that mechanical load is required to regulate growth plate function including proliferation of chondrocytes and column formation. The molecular mechanism governing proliferation and column formation in response to load are not known but may involve chondrocytes sensing mechanical changes in the environment thought their actin cytoskeleton. Unloading mouse hind limb results in disorganization of the actin structure in chondrocytes, loss of columnar structure in the growth plate, and reduced limb length. Mice with conditional deletion of genes associated with regulation of the actin cytoskeleton demonstrate similar alterations in their growth plates. These observations highlight the importance of mechanical loading on growth plate function but there is still limited understanding of the molecular mechanisms of how limb length is regulated in response to mechanical loads.Support or Funding InformationNIH/NIAMS R21 AR070097 and the US‐Israel Bi‐national Science Foundation