Submitted on September 11, 2006
Accepted on January 12, 2007
Abnormal Muscle and Hematopoietic Gene Expression May be Important for Clinical Morbidity in Primary Hyperparathyroidism (PHPT)
Sjur Reppe1, Lis Stilgren2, Bo Abrahamsen2, Ole K Olstad3, Fadila Cero3, Kim Brixen2, Lise S Nissen-Meyer1, and Kaare M Gautvik4*
1 Department of Medical Biochemistry, University of Oslo, Oslo, Norway
2 Department of Endocrinology, Odense University Hospital, Odense, Denmark
3 Deptartment of Clinical Chemistry, Ullevaal University Hospital, Oslo, Norway
4 Department of Medical Biochemistry, University of Oslo, Oslo, Norway; Deptartment of Clinical Chemistry, Ullevaal University Hospital, Oslo, Norway; Lovisenberg Hospital, Oslo, Norway
* To whom correspondence should be addressed. E-mail: k.m.gautvik{at}medisin.uio.no.
In primary hyperparathyroidism (PHPT) excess PTH secretion by adenomatous or hyperplastic parathyroid glands leads to elevated serum [Ca2+]. Patients present complex symptoms of muscular fatigue, various neuropsychiatric, neuromuscular, and cardiovascular manifestations, and in advanced disease, kidney stones and metabolic bone disease. Our objective was to characterize changes in muscle and haematopoietic gene expression in patients with reversible mild PHPT after parathyroidectomy and possibly link molecular pathology to symptoms. Global mRNA profiling using Affymetrix Gene Chips was carried out in biopsies obtained before and one year after parathyroidectomy in 7 patients discovered by routine blood [Ca2+] screening. The tissue distribution of PTH receptor mRNAs (PTHR1 and PTHR2) were quantitated using real time RT-PCR in unrelated persons to define PTH target tissues. Of about 10 000 expressed genes, 175 muscle, 169 haematological and 99 bone associated mRNAs were affected. Notably, the major part of muscle related mRNAs was increased while haematological mRNAs were predominantly decreased during disease. Functional and molecular network analysis demonstrated major alterations of several tissue characteristic groups of mRNAs as well as those belonging to common cell signaling and major metabolic pathways. PTHR1 and PTHR2 mRNAs were more abundantly expressed in muscle and brain than in haematopoietic cells. We suggest that sustained stimulation of PTH receptors present in brain, muscle and haematopoietic cells have to be considered as one independent, important cause of molecular disease in PHPT leading to profound alterations in gene expression which may help explain symptoms like muscle fatigue, cardiovascular pathology and precipitation of psychiatric illness.
