| Turnover of cells and matrix occurs in all organs and tissues and is essential to maintain their health and quality. In bone, cell and matrix turnover occur simultaneously through remodeling, wherein resorption removes and osteoblastic infilling replaces microscopic regions of bone. Removal and replacement of microscopic regions of bone that have reached the end of their functional life is known as targeted remodeling. This loss of local functionality in bone is readily exemplified by the presence of microdamage from wear and tear. Left unremodeled, microdamaged bone has compromised mechanical properties that are implicated in stress fractures, bone graft failures, and bone fragility in aging. How remodeling targets area of bone for replacement is not known. The aim of this work is to determine whether osteocytes, the cells that are buried within bone matrix, play an active role in regulating targeted remodeling. Studies from our laboratory indicate that osteocyte apoptosis in response to microdamage is required for intracortical remodeling to occur. However, the clinical observation is that dead bone doesn't resorb (bone grafts, prosthetic interface failure, the femoral head in avascular necrosis) suggesting that active signaling is also required for intracortical remodeling to occur. Two questions arise from these observations: (1) do osteocytes produce the necessary chemical signals that attract osteoclast precursors from bone marrow and periosteal vessels? and (2) once activated, do osteocytes potentially regulate the activity of osteoclasts? To address these questions, we fatigue loaded rat ulnae to introduce microdamage. We found that early after induction of microdamage, osteocytes show increased RANKL and VEGF-A message and protein with a concomitant decrease in OPG message and protein. Previously, this function was attributed to osteoblasts and bone lining cells. Osteocytes, whose function in local control of bone remodeling was unclear, now, seem to play a crucial role in activating bone remodeling and thereby, repair of wear and tear bone injury, by producing osteoclastogenic regulators in a temporally and spatially relevant manner. |
