The role of mast cells in parathyroid bone disease.
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.
Turner
Russell T
RT
Department of Nutrition and Exercise Sciences, Oregon State University, Corvallis, OR 97331, USA. Russell.Turner@oregonstate.edu
Iwaniec
Urszula T
UT
Marley
Kevin
K
Sibonga
Jean D
JD
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001549:Benzamides; D001851:Bone Diseases, Metabolic / Q000209:etiology*; D001853:Bone Marrow / Q000473:pathology / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D006961:Hyperparathyroidism / Q000150:complications*; D000068877:Imatinib Mesylate; D008297:Male; D008407:Mast Cells / Q000502:physiology*; D051379:Mice; D008875:Middle Aged; D010002:Osteitis Fibrosa Cystica / Q000209:etiology / Q000473:pathology; D010281:Parathyroid Hormone / Q000494:pharmacology / Q000502:physiology*; D044162:Parathyroid Hormone-Related Protein; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014192:Trapidil / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; D001549:Benzamides; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D011743:Pyrimidines; C075278:platelet-derived growth factor A; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D014192:Trapidil; D000077191:Wortmannin