Mechanotransduction determines the structure and function of lung and bone: a theoretical model for the pathophysiology of chronic disease.

Multicellular organisms have evolved in adaptation to the Earth's gravitational and oxygen environment. This epigenetic process is dependent on the capacity of mesodermal cells to act as mechanosensors that can conform, deform, and reform in adaptation to the organism's physical environment. Mechanical forces, such as hydrostatic pressure and gravity, play important roles in the embryonic development, homeostasis, and repair of lung and bone. We discuss the role of parathyroid hormone-related protein (PTHrP) as a mechanotransducer for stretch in these organs during normal development, particularly as it lends itself to homeostasis; we further demonstrate that "uncoupling" of such mechanisms may play a central role in injury repair, particularly as it relates to chronic diseases of lung and bone. Endothermal PTHrP signaling through its G-protein coupled receptor promotes normal cell-cell signaling that maintains the homeostatic phenotypes of lung and bone. Molecular disruption of the PTHrP/PTHrP receptor pathway from endoderm to mesoderm, because of such factors as volutrauma, hyperoxia, inflammation, and microgravity, alters intracellular signaling, causing maladaptive cellular changes, resulting in myofibroblast proliferation and granulation. Examples of such pathologic changes specifically related to this cellular/molecular mechanism of maladaptation are chronic lung disease and osteoporosis. We suggest a new paradigm that may help in the future creation of diagnostic and therapeutic modalities for a wide range of developmental and chronic diseases ranging from bronchopulmonary dysplasia in newborns to idiopathic pulmonary fibrosis and osteoporosis as a result of aging or microgravity.