| Bone remodeling is the coupled matrix turnover process, wherein osteoclasts remove a small packet of bone and osteoblasts then refill the microscopic void. Elevated bone remodeling—e.g. after estrogen loss, glucocorticoid administration or with fatigue microdamage—leads to osteoporosis. Therefore, understanding the signal that targets bone remodeling units is essential. Our studies show that apoptosis, i.e. programmed cell death, of osteocytes, the resident cells in the bone matrix, occurs in co-localization with damaged bone regions that are subsequently remodeled, and therefore, osteocyte apoptosis is thought to play a key role in the targeting mechanism. Moreover, we have shown inhibition of osteocyte apoptosis in vivo in association with microdamage by a general caspase-inhibitor, Z-VAD-FMK. At 24 hours after fatigue, sections from non-treated animals showed dramatically increased numbers of osteocytes staining TUNEL-positive (i.e. apoptosic), and expressing Fas, FasL and Caspase-3 in bone surrounding microdamage. In contrast, sections from animals treated with Z-VAD-FMK showed same low TUNEL-positive staining and Caspase-3 expression in osteocytes near microdamage as in osteocytes in fatigued ulnae distant from microdamage and in nonloaded, control bone. Fas and FasL expression in osteocytes near microdamage remained elevated after treatment with Z-VAD-FMK. These results demonstrate that osteocyte apoptosis can be inhibited by a caspase-inhibitor in vivo, which can provide possible new therapeutical intervention with targeted bone resorption after fatigue. |
