Abstract
Chronic hyperparathyroidism (HPT) is a common cause of metabolic bone disease. These studies investigated the underlying cellular and molecular mechanisms responsible for the detrimental actions of elevated parathyroid hormone (PTH) on the skeleton. Bone biopsies from hyperparathyroid patients revealed an association between parathyroid bone disease and increased numbers of bone marrow mast cells. We therefore evaluated the role of mast cells in the etiology of parathyroid bone disease in a rat model for chronic HPT. In rats, mature mast cells were preferentially located at sites undergoing bone turnover, and the number of mast cells at the bone–bone marrow interface was greatly increased following treatment with PTH. Time-course studies and studies employing parathyroid hormone–related peptide (PTHrP), as well as inhibitors of platelet-derived growth factor-A (PDGF-A, trapidil), kit (gleevec), and PI3K (wortmannin) signaling revealed that mature mast cell redistribution from bone marrow to bone surfaces precedes and is associated with osteitis fibrosa, a hallmark of parathyroid bone disease. Importantly, mature mast cells were not observed in the bone marrow of mice. Mice, in turn, were resistant to the development of PTH-induced bone marrow fibrosis. These findings suggest that the mast cell may be a novel target for treatment of metabolic bone disease. © 2010 American Society for Bone and Mineral Research.
Highlights
Hyperparathyroidism (HPT), a common endocrine disorder, results in a spectrum of skeletal abnormalities ranging from increased bone turnover in individuals with mild HPT to parathyroid bone disease in patients with severe chronic HPT.[1,2] In individuals with severe primary or secondary chronic HPT, bone marrow–derived preosteoblasts exhibiting a fibroblast-like morphology migrate to bone surfaces, where they produce copious quantities of poorly organized extracellular matrix, which is a hallmark of high-turnover parathyroid bone disease
The results suggest that mast cell accumulation onto bone surfaces in response to elevated parathyroid hormone (PTH) and their interaction with osteoblast lineage cells via pathways involving PDGF receptor-a, c-kit, and PI3K signaling precede and contribute to PTH-induced peritrabecular fibrosis
PTH increases mast cell number and secretion of mast cell–derived preformed effectors in rats.[38,39] To date, studies have emphasized the role of mast cell–derived histamine in osteoclastogenesis and bone resorption.[40,41,42,43,44] The role of mast cells in osteoblast differentiation and HPT-induced bone marrow fibrosis has received less attention
Summary
Hyperparathyroidism (HPT), a common endocrine disorder, results in a spectrum of skeletal abnormalities ranging from increased bone turnover in individuals with mild (asymptomatic) HPT to parathyroid bone disease in patients with severe chronic HPT.[1,2] In individuals with severe primary or secondary chronic HPT, bone marrow–derived preosteoblasts exhibiting a fibroblast-like morphology (fibroblasts) migrate to bone surfaces, where they produce copious quantities of poorly organized extracellular matrix, which is a hallmark of high-turnover parathyroid bone disease. We developed a model for severe HPT in which PTH is continuously administered using a subcutaneous osmotic pump.[8] Within 1 week, the rats developed a skeletal pathology characterized by elevated bone turnover, defective matrix mineralization, and severe peritrabecular fibrosis.
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