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# Disorders of the skeletal system and bone remodeling

## Problem

Despite their hard, persistent nature and relatively static proportions, human bones are an extraordinarily dynamic tissue that is continuously resorbed, remodeled, and renewed. The maintenance of these processes requires precisely regulated homeostatic mechanisms in order to preserve adequate bone strength, structure, and density.
Bone resorption is triggered by parathyroid hormone (PTH) under conditions of low calcium. PTH binds to receptors on osteoblasts which upregulate the expression of the signalling protein RANKL. RANKL binds to the receptor RANK on osteoclast precursors, activating the transcription factor Nf-kB, which signals them to differentiate and activate into functioning osteoclasts. OPG, produced in osteoblasts, competitively blocks RANKL, thereby preventing signaling. Because of this, net bone formation or resorption can be said to be a function of the ratio of OPG to RANKL. Osteoblasts synthesize and arrange bone matrix proteins, their chief role being to deposit collagen and other proteins to form new bone. These important interactions are shown in Figure 1.
Figure 1: Key cells and signaling molecules in bone remodeling. Osteoblasts drive bone formation while osteoclasts drive bone resorption. Osteoclast differentiation and activation involves signals from PTH, receptor-ligand interaction with RANK and Nf-kB activation.
Several diseases are known in which some part of this process has been disturbed, and thus proceeds out of balance. Osteoporosis is a disease characterized by decreased bone density and a change in bone structure wherein the bones become increasingly porous. Osteoporosis affects over half of the population of the United States over 50 years old and is overwhelmingly more common among postmenopausal women, largely due to the marked decrease in estrogen levels. Estrogen plays an important role in regulating levels of RANKL and OPG.
Autosomal recessive osteopetrosis (ARO) on the other hand, often referred to as “marble bone disease”, is characterized by excessively thick and dense, albeit brittle, bones. ARO is a congenital condition, affecting individuals from birth due to a number of genetic anomalies, typically resulting in death by the age of ten. One variant results from a mutation in the gene coding for RANKL; others from defects in OPG. A hypothetical study hopes to determine the epidemiology of osteoporosis and ARO in the United States, and attaches a survey to an annual political election ballots routinely over ten years, with a yearly sample size of nearly 10 start text, m, i, l, l, i, o, n, end text. The survey asks simple yes/no questions regarding if the individual (the voter) has ever had either of the two conditions. The results are shown in Table 1.
Table 1: Epidemiology of bone remodeling disorders. The survey responses for three selected years of the ten year sampling period are shown. Percentages represent the frequency of the indicated response out of all potential respondents (all voters), reported to the nearly tenth of a percent. Blank surveys, illegible surveys, and responses indicating a response of “Unsure” account for the remaining percentage of potential respondents, and are not shown in the Table.
Assuming each disease is due to a single defect in cells involved in bone turnover, what are the most likely defects in osteoporosis and osteopetrosis, respectively?