A 67-year-old man comes to the office with right tibial pain that started 3 months ago and has increased in intensity over time. He also has had progressive hearing impairment for the last year. Physical examination reveals local tenderness and a lumpy protuberance over the right tibia. After extensive evaluation, the patient undergoes a bone biopsy. The pathologist identifies numerous multinucleated cells, some containing over 100 nuclei. Which of the following factors is essential for the differentiation of the cells described by the pathologist?

Question

A 67-year-old man comes to the office with right tibial pain that started 3 months ago and has increased in intensity over time.  He also has had progressive hearing impairment for the last year.  Physical examination reveals local tenderness and a lumpy protuberance over the right tibia.  After extensive evaluation, the patient undergoes a bone biopsy.  The pathologist identifies numerous multinucleated cells, some containing over 100 nuclei.  Which of the following factors is essential for the differentiation of the cells described by the pathologist?

Quizplus · Accepted Answer

11ec160b_3d04_35c7_9249_5d75ade7e165_MD0001_00 This patient has pain and deformity of the long bones with hearing loss (due to bony deformity of the skull); these are typical features of Paget's disease of bone. The initial abnormality in Paget's disease is excessive osteoclastic bone resorption followed by increased bone formation by osteoblasts; this results in high bone turnover in the affected areas. The new bone formation is disorganized, and pagetic bone lesions typically appear on imaging as thickened areas of mixed sclerosis and lucency. Osteoblasts are cells with a single nucleus that arise from mesenchymal stem cells found in the periosteum and bone marrow. In contrast, osteoclasts originate from the mononuclear phagocytic cell lineage and are ultimately formed when several precursor cells fuse to create a multinucleated mature cell. Osteoclasts in Paget's disease are typically very large and can have up to 100 nuclei (normal osteoclasts have 2-5). The 2 most important factors for osteoclastic differentiation, macrophage colony-stimulating factor (M-CSF) and receptor for activated nuclear factor kappa-B ligand (RANK-L), are produced by osteoblasts and bone marrow stromal cells. Osteoprotegerin (OPG) is a physiologic decoy receptor that decreases binding of RANK-L to RANK. Inhibition of RANK-L to RANK receptor interaction reduces the differentiation and survival of osteoclasts, resulting in decreased bone resorption and increased bone density (Choice C). OPG loss-of-function mutations cause juvenile Paget's disease. A monoclonal antibody (denosumab) that inhibits the RANK/RANK-L interaction also leads to increased bone density and is commonly used for the treatment of osteoporosis. (Choice A) Fibroblast growth factors (FGFs) regulate chondrogenesis and osteogenesis. FGFs induce proliferation of osteoblastic precursor cells and anabolic function of mature osteoblasts. Abnormalities in the FGF receptor result in the congenital short-limbed dwarfism known as achondroplasia. (Choice B) Insulin-like growth factors (IGF-I and IGF-II) are synthesized by various tissues, including the liver and bone. IGF-I increases osteoblastic replication and collagen synthesis; it also decreases collagen degradation by inhibiting the enzyme matrix metalloproteinase-13 (MMP-13). The net effect of IGF-I on the bone is anabolic. (Choice E) Transforming growth factor beta increases the replication of osteoblast precursors, leading to increased formation of mature osteoblasts. Transforming growth factor beta also increases collagen synthesis and decreases bone resorption by increasing osteoclastic apoptosis. Educational objective: Osteoclasts originate from hematopoietic progenitor cells. Macrophage colony-stimulating factor and receptor for activated nuclear factor kappa-B ligand (RANK-L) play an important role in osteoclast differentiation. Paget's disease of bone is characterized by increased numbers of abnormal osteoclasts, excessive bone turnover and disorganized bone remodeling. __________ References: Regulation of NFATc1 in osteoclast differentiation. (http://www.ncbi.nlm.nih.gov/pubmed/25489571)

A 67-Year-Old Man Comes to the Office with Right Tibial