Biochemistry Flashcards
How does multiple myeloma cause bone pain and bone lesions?
Neoplastic plasma cells activate the RANK receptor on osteoclasts, which in leading to bone destruction.
Normal bone physiology:
In healthy adults, bone physiology is a dynamic, coordinated process controlled by 2 types of cells: osteoclasts and osteoblasts. Through a balanced remodeling process, osteoclasts resorb bone, and osteoblasts build bone at the same site.
The bone remodeling sequence consists of 4 distinct phases: activation, resorption, reversal, and formation. Several members of the tumour necrosis factor (TNF) super-family of proteins are key participants in the complex series of events that results in the ability of mature osteoclasts to resorb bone. RANK, RANK Ligand, and osteoprotegerin (OPG) all work together to regulate osteoclast function. Expressed by osteoblasts and stromal cells, RANK Ligand binds to the RANK receptor on osteoclast precursors set in motion their differentiation into (mature) osteoclasts. When this occurs, prefusion osteoclasts mature to multinucleated osteoclasts.At the bone surface, RANK Ligand activates the osteoclasts and suppresses apoptosis.
Several factors can initiate osteoclast formation, including parathyroid hormone, prostaglandins, IL-1 and IL-6, and colony-stimulating factors. Most of these, however, stimulate osteoclastogenesis by up-regulating the expression of RANK Ligand on the surface of marrow stromal cells and immature osteoblasts.
To maintain the balance between bone formation and bone resorption, the body naturally produces OPG, secreted by osteoblasts. By binding with RANK Ligand, OPG prevents RANK Ligand from binding with RANK on the surface of osteoclasts and their precursors. This process is governed by cytokines and hormones, and ultimately determines osteoclast activity. Seen in this light, OPG is important in the regulation of osteoclast formation and bone resorption.
Metastatic Bone Disease
In metastatic bone disease, RANK Ligand has been implicated in a “vicious cycle” of bone destruction and tumour growth. Some tumours that have metastasized to the bone produce growth factors that can increase expression of RANK Ligand by osteoblasts. This stimulates osteoclast activity and leads to excess bone loss.
Osteoclast-mediated bone resorption leads to the release of growth factors and calcium from the bone matrix, that can in turn stimulate the tumour cell, further contributing to this cycle of bone destruction.
Clinically, bone metastases can be associated with considerable skeletal morbidity. This may include radiation therapy for bone pain, surgical intervention, pathologic fracture, spinal cord or nerve root compression, and hypercalcemia of malignancy (HCM).
