Passage Bone remodeling is the continuous, microscopic process by which bone tissue throughout the body is resorbed and re-deposited. Proper regulation of bone remodeling is necessary to maintain bone strength and prevent the onset of conditions of fragile bone such as osteoporosis. Patients with such conditions have increased fracture risk and generally exhibit decreased activity of osteoblasts (bone-depositing cells), leading to reduced bone density and weakening of the bone matrix. However, some cases can occur due to overactive osteoclasts (multinucleated cells that mediate bone resorption). Osteoclasts resorb bone by secreting proteolytic enzymes and acids into the adjacent extracellular space. These enzymes degrade the organic matrix of bone, and the acid causes the dissolution and release of the mineral components of bone, such as calcium, potassium, and magnesium. Generally, less than 1% of adult bone is occupied by active osteoclasts.Osteoclast differentiation and activation is thought to be related to the RANK/RANKL signaling pathway. RANKL, expressed as a membrane-bound or secreted protein, serves as the ligand for RANK, a transmembrane receptor. In bone tissue, RANK is expressed by precursors of mature osteoclasts, also known as osteoclast progenitor cells (OPCs). RANKL is expressed by osteoblasts adjacent to OPCs, and the binding of RANKL to RANK in these neighboring cells causes downstream effects through recruitment of TRAF6, an intracellular protein. TRAF6 activates multiple downstream signaling cascades, but only four of these directly mediate the development of mature osteoclasts from OPCs. In one of the four pathways, the transcription factor NF-kB is activated, which leads to increased expression of the proto-oncogene c-Fos. Subsequently, c-Fos interacts with another transcription factor known as NFATc to promote the expression of genes related to osteoclast-specific development and function in OPCs (Figure 1). Figure 1 RANK/RANKL signaling induces differentiation of OPCs into osteoclasts -Cathepsin K is a proteolytic enzyme secreted by osteoclasts. In a clinical trial, patients with osteoporosis due to increased RANK-RANKL signaling are divided into an untreated group (saline placebo administered) and a treated group (cathepsin K inhibitor administered). Given the information in the passage, bone density after the trial will most likely be:

Question

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11ecba2d_1006_8498_a3bf_951e5870adb7_MD0008_00 According to the passage, some cases of osteoporosis (a fragile bone condition) arise due to overactive osteoclast activity. The passage states that osteoclasts are cells that break down (resorb) bone and that binding of RANK to RANKL induces osteoclast progenitor cells (OPCs) to differentiate into mature osteoclasts. These mature osteoclasts secrete acids that demineralize bone and express osteoclast-specific genes, such as those encoding the proteolytic enzymes (eg, cathepsin K) responsible for degrading the organic bone matrix. In the given scenario, patients with osteoporosis due to increased RANK-RANKL signaling were split into the following two groups during a clinical trial: an untreated group, which received a saline placebo a treated group, which received a drug that inhibits cathepsin K, a proteolytic enzyme secreted by osteoclasts to break down the bone matrix When untreated patients were given the saline (placebo), their heightened RANK/RANKL signaling most likely remained unchanged. As a result, RANK/RANKL-induced OPC differentiation into osteoclasts continued in untreated patients. This allowed osteoclasts to increase in number and secrete cathepsin K to break down bone, leading to the characteristic of decreased bone density seen in untreated osteoporosis. In contrast, when the treated group was given the cathepsin K inhibitor, this inhibitor prevented cathepsin K from breaking down bone in these patients, increasing their bone density over time. Accordingly, cathepsin K activity would be decreased in patients treated with the inhibitor but remain overactive due to increased RANK/RANKL signaling in untreated patients with osteoporosis. As a result, after the trial, bone density would be decreased in the untreated group compared to the treated group (Choices A, C, and D). Educational objective: During bone resorption, osteoclasts release proteolytic enzymes that break down the organic bone matrix. In osteoporosis patients, overactivity of osteoclasts and increased release of these enzymes can lead to decreased bone density across time.

Passage Bone Remodeling Is the Continuous, Microscopic Process by Which Bone