Bone resorption is accomplished by two cellular elements of the skeletal system; osteoclytic osteocytes, the primary mediators of the skeletal contribution to mineral homeostasis, and osteoclasts, surface cells primarily concerned with bone remodeling for mechanical strength. The ia (incisors absent) rat is a mutant that has a disease known as congenital osteopetrosis--a skeletal defect resulting from an abnormal accumulation of bone due to decreased bone resorption. This mutant has osteoclasts, but they are abnormal, lacking a ruffled border--the site of normal bone resorption. Evidence from our laboratory indicates that normal osteoclastic function and bone remodeling can be restored in the ia mutant by transplanting mononuclear cells isolated from the spleen and thymus of normal littermates. I propose to determine whether the transplanted cells are the precursor of the osteoclast by transplanting mononuclear cells from normal littermates, labelled with 3H-thymidine, into ia mutants, to see if labelled osteoclastic nuclei can be identified in alveolar bone. An alternative hypothesis is that the cells may be providing a local influence or cellular product that modulates normal osteoclastic activity. The possibility can be tested by transplanting lethally-irradiated, mitotically-inhibited, or differentiation-inhibited mononuclear cells from normal littermates into ia rats. The mononuclear cellular population will be further subdivided into monocytes and various subpopulation of lymphocytes to further deliniate the cellular source of the cure. Finally, the scope of the disease will be investigated by evaluating the other phagocytic cells in the ia rat to determine if the cellular defect is found only in the osteoclast or present in some hematopoietic stem cell, resulting in a more generalized defect. These experiments should be useful in understanding normal and modulating abnormal osteoclastic function, and could be relevant to the treatment of a number of bone pathologies such as osteoporosis (loss of bone) and periodontal disease--the irreversible loss of alveolar bone. The most direct application of this study is the possibility of using the transplantation of mononuclear cells to cure the malignant-juvenile form of human osteopetrosis.
NIH ExPorter
NIH ExPorter