Pseudohypoparathyroidism (PHP) is characterized by a lack of response to ... normal skeletal responsiveness to PTH in some patients with PHP type Ia was ...
JOURNAL O F BONE AND MINERAL RESEARCH Volume 11, Number I, 1996 Blackwell Science, Inc.
Normal Parathyroid Hormone Responsiveness of Bone-Derived Cells from a Patient with Pseudohypoparathyroidism SOPHIA ISH-SHALOM,' LETITIA G. RAO,'.' MICHAEL A. LEVINE,' DONALD FRASER,' SANG W. KOOH,' ROBERT G. JOSSE,' ROBERT McBROOM,'." MIN-MIN WONG,? and TIMOTHY M.MURRAY,'
ABSTRACT Pseudohypoparathyroidism (PHP) is characterized by a lack of response to parathyroid hormone (PTH); however, normal skeletal responsiveness to PTH in some patients with PHP type Ia was previously suggested on the basis of clinical observations. To test this hypothesis, we measured cyclic adenosine monophosphate (CAMP)production in response to various agonists in bone-derived osteoblast-like (OBL) cells from trabecular explants obtained from an iliac crest biopsy of a 25-year-old woman with PHP. The patient was proved to have PHP type la on the basis of Albright's hereditary osteodystrophy and decreased activity of stimulatory guanine nucleotide-binding protein (C,) in erythrocytes. Responsiveness of the patient's OBL cells was compared with OBL cells from eight subjects aged 18-39 years who had no evidence of metabolic bone disease. OBL cells from the patient responded to the following agonists (expressed in multiples of elevation of CAMP,stimulatedibasal, mean f SE, n = 3): PTH, 3.8 f 0.3; forskolin, 8.2 f 0.2; and cholera toxin, 56.8 f 10.0. These responses were not significantly different from those of control OBL cells: PTH, 4.5 & 1.1 (range 2.4-7.5); forskolin, 7.7 f 1.4; and cholera toxin, 57.9 & 16.2. The normal cholera toxin response indicated the presence of functional G,. Bone cells from patients with PHP type Ia may exhibit a normal PTH receptor-coupled adenylyl cyclase system in vitro despite clinical evidence of impaired hormone-responsive adenylyl cyclase in other tissues, including the kidney. Skeletal responsiveness to FTH may explain the long periods of spontaneous normocalcemia observed in this patient. (J Bone Miner Res 1996;11:f&14)
a phosphaturic or nephrogcnous cyclic adenosine monophosphate (CAMP)response to PTH, whereas subjects with PHP type I1 fail to show phosphaturia despite a normal nephrogenous CAMP responsc to PTH.'" Skeletal resistance to PTH in patients with PHP type I has been inferred on the basis of hypocalcemia, despite elevated PTH and ;I subnormal calcemic response to prolonged intramuscular administration of PTH.(3) Apparent skeletal resistancc to PTH has been assumed t o result from an abnormality in
INTRODUCTION (PHP) was first described by Albright ct al.(') as a disease characterized by biochemical signs of hypoparathyroidism, hypocalcemia, and hyperphosphatcmia due to target organ resistance to parathyroid hormone (PTH). Subtypes o f the disease, differentiated according to the mechanism underlying the renal resistance, havc been recognized: subjects with PHP type I fail to show
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'Department of Endocrinology, Rambam Medical Center and The Bruce Rappaport Faculty of Medicine. Technion-Isracl Institute o f Tcchnology, Haifa, Israel. 'Division o f Endocrinology and Metabolism, St. Michael's Hospital. Toronto, Ontario, Canada. 'Department of Medicine. Univcrsity of Toronto and Research Institute. Queen Elizabeth Hospital. Toronto, Ontario, Canada. 'Division o f Endocrinology and Metabolism, Johns Hopkins University School of Medicine, Baltimorc. Maryland. U.S.A. 5Dcpartment of Surgery, St. Michael's Hospital. Toronto, Ontario, Canada. "Dcpartment o f Surgery, University o f Toronto and Research Institute, Queen Elizabeth Hospital, Toronto, Ontario. Canada. 8
YIH RESPONSIVENESS OF HONE CELLS IN PHP
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CAMPgcncration iri hone tissue that is similar to that which occurs in other tissues. tlowcver, radiogriiphic and histologic findings o f Iiyperparathyroid hone disease," -'') ;IS well :is cvidcncc o f diniinishcd hone density' I"' and elevated I>iochemical m r k c r s o f hone (urnover.' I ' . " ) havc provided cvidcncc o f cuccssive PTH action on bone in a t least sonic p;iticiits with Pt1P. Patients with f'l It' type la havc Albright's hereditary ostcodystrophy (Aft(>). ;I distinctive phenotype that includes short stocky build. r o t i t i d facies, hrachyductyly. and suhcutancotis ossifications. These patients iilso have reduced expression o r function o f
