Disorders of bone remodeling
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Disorders of bone remodeling
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[post_date] => 2024-12-23 18:16:56
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[post_content] => Practice Passage (Question 1-6)
*This passage is the property of Khan Academy and has been reformatted into an AAMC-style interface in their entirety by MedLife Mastery. MedLife Mastery does not endorse and is not an affiliate of Khan Academy.
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:
- 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.
- 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.
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[question] => 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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[answer] => 2
[description] => Reason for Correct Answer:
According to the passage, osteoporosis is characterized by decreased bone density. This could be due to increased bone resorption or decreased bone formation.
On the other hand, ARO is characterized by excessively dense bones. This could mean either decreased bone resorption or increased bone formation.
Of the answer choices, the only thing that makes sense with the symptoms of the disease is that osteoporosis is due to increased function of osteoclasts (thus more bone resorption) and ARO is due to the decreased function of osteoclasts (thus less bone resorption).
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[each_answer] => A. Osteoporosis is due to increased function of osteoblasts, whereas ARO is due to decreased function of osteoblasts.
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[each_answer] => B. Osteoporosis is due to increased function of osteoclasts, whereas ARO is due to decreased function of osteoclasts.
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[each_answer] => C. Both osteoporosis and ARO are due to decreased function of osteoclasts.
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[each_answer] => D. Both osteoporosis and ARO are due to increased function of osteoblasts.
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[1] => Array
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[quiz_unique_key] => 1403770772
[question] => From what primary, embryological germ layer are osteoblasts derived?
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[answer] => 3
[description] => Reason for Correct Answer:
The ectoderm forms the nervous system and skin.
The neural crest is derived from the ectoderm.
The endoderm forms visceral organs.
Bone and its components are derived from the mesoderm, which also creates muscles, the kidneys, blood and blood vessels. The germ layers are summarized in the table below, available at https://commons.wikimedia.org/wiki/File:419_420_421_Table_04_01_updated.jpg.
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[each_answer] => A. Endoderm
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[each_answer] => B. Ectoderm
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[each_answer] => C. Mesoderm
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[each_answer] => D. Neural crest
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[quiz_unique_key] => 1403770772
[question] => ARO is associated with mutations in RANKL and OPG. What structural or functional changes in RANKL and OPG would most likely be found in ARO?
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[answer] => 1
[description] => Reason for Correct Answer:
Functional OPG serves to block RANKL from binding RANK.
According to the passage, RANKL and its receptor cause increased osteoclast activity.
On the other hand, OPG blocks the RANKL receptor and therefore causes decreased osteoclast activity.
Therefore, in ARO, which is characterized by thick bones and likely decreased osteoclast activity, it’s most likely that RANKL has decreased affinity for its receptor and/or there is increased production of OPG
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[answers] => Array
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[each_answer] => A. Decreased affinity of RANKL for its receptor and increased production of functional OPG
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[each_answer] => B. Increased affinity of RANKL for its receptor and decreased production of functional OPG
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[each_answer] => C. Decreased affinity of RANKL for its receptor and decreased production of functional OPG
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[each_answer] => D. Increased affinity of RANKL for its receptor and increased production of functional OPG
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[quiz_unique_key] => 1403770772
[question] => What is the effect of increased PTH secretion?
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[answer] => 4
[description] => Reason for Correct Answer:
As shown in the passage, the effect of PTH is to increase the activity of osteoclasts.
You should also know from your MCAT studies that PTH has a variety of functions, including increasing bone resorption and, in the kidney, increasing calcium reabsorption and decreasing phosphate reabsorption.
Overall, PTH acts to increase free calcium levels in blood serum.
Reason for Incorrect Answer:
A. PTH does cause the release of phosphorus, with calcium, from bone, but because it also acts on the kidney to increase phosphorus excretion, the net effect of PTH is to lower serum phosphorus levels.
B. The passage describes PTH stimulating osteoclasts by upregulating RANKL.
C. The passage does not suggest that PTH affects OPG expression.
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[each_answer] => A. Increased serum phosphate
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[each_answer] => B. Increased osteoclast inhibition
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[each_answer] => C. Increased OPG expression
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[each_answer] => D. Increased free calcium
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[quiz_unique_key] => 1403770772
[question] => According to the information in the passage, estrogen most likely has what effect?
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[answer] => 2
[description] => Reason for Correct Answer:
The passage states that osteoporosis, which causes bone loss (decreased bone density), can be caused by a decrease in estrogen following menopause.
This suggests estrogen helps to promote bone formation. So, you’re looking for an answer that would promote bone formation.
Look at the pathway to see which factors promote bone formation. Remember that osteoblasts build bone and osteoclasts break it down.
The only answer choice that would promote bone formation is upregulation of OPG expression. As shown in the figure, OPG blocks the activation of osteoclasts. Upregulating OPG decreases osteoclast activity and decreases bone resorption.
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[each_answer] => A. Upregulation of RANKL expression
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[each_answer] => B. Upregulation of OPG expression
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[each_answer] => C. Stimulation of PTH release
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[each_answer] => D. Activation of Nf-kB
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[quiz_unique_key] => 1325138223
[question] => Which treatment is LEAST likely to be helpful for treating osteoporosis?
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[answer] => 4
[description] => Reason for Correct Answer:
The passage states that osteoporosis results in bone loss (decreased density). Therefore, you’re looking for treatment options that would increase bone formation.
The passage also states that osteoporosis is caused by a drop in estrogen levels, so you can expect that an estrogen receptor agonist may help counter this.
A RANKL inhibitor could also help, because, as shown in the passage, RANKL activates osteoclasts. Blocking RANKL will decrease osteoclast activity and decrease bone resorption.
A vitamin D analog could also help because vitamin D stimulates calcium absorption in the intestine. This helps to promote bone formation by increasing calcium levels in the blood. (And thus decreasing PTH activity.)
Because calcitonin functions to increase bone formation (modestly), a calcitonin inhibitor would NOT help treat osteoporosis.
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[each_answer] => A. A RANKL inhibitor
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[each_answer] => B. A vitamin D analog
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[each_answer] => C. An estrogen receptor agonist
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[each_answer] => D. A calcitonin inhibitor
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Figure 1
