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Course: MCAT > Unit 2

Lesson 3: Foundation 3: Organ Systems

Skeletal system: Disorders of bone remodeling

Problem

Despite its hard, persistent nature and relatively static proportions, human bone is an extraordinarily dynamic tissue that is continuously being resorbed, remodeled, and renewed. The maintenance of these processes requires precisely regulated homeostatic mechanisms 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, upregulating the expression of the signaling 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. These important interactions are shown in Figure 1.
Figure 1 Key cells and signaling molecules in bone remodeling
Diseases that occur when part of this process is disrupted include:
  1. Osteoporosis – this disease is characterized by decreased bone density and a change in bone structure wherein bones become increasingly porous. Osteoporosis affects more than half of the population of the United States over the age of 50 and is significantly more common in postmenopausal women, largely due to the marked decrease in estrogen levels.
  2. Autosomal recessive osteopetrosis (ARO) – often referred to as “marble bone disease”, this 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 is caused by a mutation in the gene coding for RANKL; others result from defects in OPG.
Assuming each disease is due to a single defect in cells involved in bone turnover, what are the most likely defects in osteoporosis and ARO, respectively?
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