Osteoporosis is a severe health problem that is associated with aging and caused, in part, by age-related changes in the normal processes of bone maintenance. The process of bone tissue turnover, or bone remodeling, is a highly regulated process where a packet of either trabecular or cortical calcified bone matrix is removed by osteoclasts and subsequently replaced by osteoblasts. As a step in the formation of the collagenous matrix of the bone, a fraction of the osteoblasts are buried in the matrix and become osteocytes. The osteocytes partially regulate mineralization and are the key candidates as the mechanosensory cells of bone. Understanding the cycle of remodeling and the signals that control it is important to determining the underlying causes of the universal age-related loss of bone mass that can cause osteoporosis, debilitating fracture and death. The remodeling process is intimately associated with angiogenesis and can be initiated and is regulated by mechanical loading. Each site of remodeling, both for cortical and cancellous tissue, is associated with the growth of a sinusoid (capillary). The sinusoids are formed, in part, of endothelial cells and serve as channels to transport nutrients, cells, and in particular, osteoclast precursors (monocytes to appropriate locations. The coordination of remodeling includes components of control resulting from: a) direct communication between osteoclasts and osteoblasts, b) vascular ingrowth, c) activation and release of growth factors sequestered in the calcified matrix and d) a collection of signals caused by mechanical loading, sex hormones or damage associated with osteocytes. The interaction between mechanical loading, osteocyte morphology and the concentration of matrix-sequestered growth factors are the potential control mechanisms to be investigated in the proposed research. The Principal Investigator proposes to determine the associations between mechanical strain at the trabecular level, osteocyte lacunar density, remodeling rate and matrix sequestered growth factors (in particular TGF-beta1, TGF-beta2, VEGF and IGF-1). The investigators have demonstrated gender related differences in osteocyte lacunar density of human vertebral cancellous bone. This is similar to the gender related difference in matrix TGF-beta1 concentration in human vertebral cancellous bone. Studies are proposed to determine the quantitative relationship between these independent findings of gender differences and to determine the association of trabecular level strain and remodeling rate to these novel results. As a further test, it will be determined whether the gender related differences noted for the vertebra are also present in tibial cancellous bone. This will help to determine whether the differences noted for the vertebra are systemic or site-specific.
