**1.3. Mechanical stimuli and osteocyte apoptosis**

26 Apoptosis and Medicine

**1.2. Mechanical stimuli in bone** 

occur in osteoblast, osteoclast and osteocytes in response to it.

out of bone. Osteoclasts are multinucleated giant cells; their role is to resorb bone. Actively resorbing osteoclasts are usually found in cavities on bone surfaces, called resorption cavities. Osteocytes are the most abundant cell type in mature bone. During bone formation some osteoblasts are left behind in the newly formed osteoid as osteocytes when the bone formation moves on. The embedded osteoblast in lacunae differentiate into osteocytes by losing much of their organelles but acquiring long, slender processes encased in the lacunarcanulicular network that allow contact with earlier incorporated osteocytes and with osteoblast and bone lining and periosteal cells lining the bone surface and the vasculature. The osteocytes are the cells best placed to sense the magnitude and distribution of strains. They are strategically placed both to respond to changes in mechanical strain and to disseminate fluid flow to transduce information to surface cells of the osteoblastic lineage via their network of canalicular processes and communicating gap junctions (Cowin, 2001).

Mechanical stimuli are one of the important regulation factors of bone remodeling. According to recent findings, osteocytes might play a role in the mechanical regulation of bone, receiving mechanical input signals and transmitting these stimuli to other cells in bone. Osteocyte is believed to comprise a sensory network that monitors mechanical load and tissue damage, and triggers appropriate adaptive responses, either formation or resorption. Mechanisms by which osteocytes could sense mechanical load have been understood by means of fluid movements throughout the lacunar-canalicular system, with some combination of shear stress and streaming potentials providing the proximate stimuli. The relations between mechanical stimuli and mature bone have been examined by experimental studies. There are suggested that higher rates of mechanical loading would evoke grater adaptive responses than lower rates of loading in mature bone (LaMonte et al., 2005). Exercise can substantially alter the physical states of a bone and generate adaptive responses. In a randomized controlled clinical trial, Fuchs et al.(2001) showed that, in jumpers, jumping significantly increases bone mineral content in femoral neck and lumbar skeleton relative to controls. McKay et al. (2000) found that jumping three times weekly for 8 months significantly augmented a real bone mineral density in the femoral trochanteric region. These studies have hypothesized that loading induced stimuli is the main signalgenerating factor and play a key role in mechanobiology. However, disuse uncouples bone formation from resorption, leading to increased porosity, decreased bone geometrical properties, and decreased bone mineral content which compromises bone mechanical properties and increases fracture risk. The removal of routine bone stresses (e.g. from immobilization, inactivity, or reduced gravity) has deleterious consequences on bone integrity. Reduced skeletal loading causes net bone loss by unbalancing bone formation and bone resorption (Takata and Yasui, 2001; Caillot-Augusseau et al., 1998). Rat hindlimb immobilization, human spaceflight, and human bedrest can all cause increased bone resorption and decreased bone formation (Caillot-Augusseau et al., 1998; Weinreb et al., 1989; Li et al., 2005; McGee et al., 2008). Therefore, the process of mechanotransduction of bone, the conversion of a mechanical stimulus into a biochemical response, is known to It is well recognized that the origin of osteocyte is osteoblasts embedded in its own matrix and some osteocytes die eventually (apoptosis). Aging, loss of estrogen, loading, and chronic glucocorticoid administration is known to increase osteocyte apoptosis and loading decreases the proportion of apoptotic osteocyte in cortical bone in rats (Noble et al., 2003; Gu et al., 2005; Delgado-Calle et al., 2011; Kennedy et al., 2012). These studies investigated the role of osteocytes in the control of loading related remodeling and they exhibited the effects on osteocyte viability of mechanical loading applied to the bone. Osteocyte apoptosis triggers osteoclast precursor recruitment to initiate bone resorption, whether it is induced by weightlessness or fatigue loading and precedes osteoclast resorption. An osteoclast/osteoblastdependent process related on the osteocytes population may participate in making the decision as to where and when a new remodeling cycle will be initiated. That is, osteocyte network could be considered the main sensor of loads. To take these observations into account, Frost proposed the concept of mechanostat (Duncan & Turner, 1995; Frost, 2003; Hughes et al., 2010). According to this concept, the authors have proposed the mathematical model for bone remodeling described in the following section.
