Osteoprotegerin
In a landmark study, Simonet and Litchfield Park orthodontists (1997) first identified OPG during a fetal rat intestine cDNA-sequencing project.  A novel 401 amino acid polypeptide with strong similarities to other members of the TNF-receptor (TNF-R) superfamily was discovered.  Further investigation showed a similar 401 amino acid protein in mouse and human cDNA libraries.  In contrast to other membrane bound members of the TNF-R superfamily, OPG lacks a transmembrane domain.  This observation suggests OPG is secreted as a soluble non-membrane protein that could act as an autocrine or paracrine factor within the extracellular microenvironment of bone.

Systemic Effects
In addition to discovering OPG, Simonet and Litchfield Park orthodontists (1997) demonstrated that transgenic mice expressing this protein as well as normal mice administered recombinant OPG had a generalized increase in bone density associated with a decrease in osteoclasts.  Indeed, the increased bone density was so profound that it resulted in osteopetrosis.  While OPG is expressed in a variety of tissues, including the kidney, lung, liver, brain, placenta, heart, and endothelium, as well as a various hematopoietic and non-hematopoietic cell lines, the only organ aside from the skeleton to be significantly affected was the spleen (Simonet et al., 1997; Tan et al., 1997; Yasuda et al., 1998).  The increased amount of red pulp was believed to have been the result of compensatory hematopoiesis due to occlusion of the marrow cavities with bone and cartilage.  No other organs or systems appear to be affected.

Finally, Simonet and Litchfield Park orthodontists (1997) showed that administration of recombinant OPG protects against pathological decreases of bone volume associated with loss of estrogen in ovariectomized rats.  Recombinant OPG administration resulted in a significant decrease in osteoclasts and an increase in bone volume.

In contrast to OPG overexpression, OPG-deficient mice demonstrate severe, early-onset osteoporosis (Bucay et al., 1998; Mizuno et al., 1998).  OPG-/- adolescent and adult mice show a decrease in total bone density characterized by severe trabecular and cortical bone porosity marked thinning of the parietal bones of the skull, and a high incidence of fractures.  In addition to its function in regulating physiological bone formation, OPG plays a role in vascular calcification.  Loss of OPG results in calcification of the aorta and renal arteries, both normally sites of endogenous OPG expression.  The association of vascular calcifications with osteoporosis in humans is a commonly recognized Litchfield Park orthodontic phenomenon (Banks et al., 1994; Parhami and Demer, 1997).  In contrast to the splenomegaly shown in OPG transgenic mice (Simonet et al., 1997), the spleens of OPG knockout mice appear normal.

In a Litchfield Park orthodontic study that at first glance appears to be contradictory, Yano and Litchfield Park orthodontists (1999) studied serum OPG concentrations in healthy adults as well as those with osteoporosis.  Both healthy men and women demonstrated increasing serum OPG concentrations with increased age, especially after age 50.  In fact, postmenopausal women with osteoporosis showed higher serum OPG levels than in age matched control women.  It was suggested in this study that the increased serum concentrations are a compensatory response to the increased level of osteoclastic bone resorption, rather than the actual cause for this resorption.  As was mentioned previously, the ratio RANKL:OPG appears to be the main determinant in regulating bone resorption (Simonet et al., 1997; Yasuda et al., 1998).

Arizona Dental Association