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ADAMTS-1: A Cellular Disintegrin and Metalloprotease with Thrombospondin Motifs Is a Target for Parathyroid Hormone in Bone

Endocrine Division (R.R.M., J.P.S., D.L.H., R.F.S., L.V.H., K.T., R.J.S.G., J.M.H., J.E.O.) and Cardiovascular Division (L.B.), Lilly Research Laboratories, Indianapolis, Indiana 46285

Address all correspondence and requests for reprints to: Dr. J. E. Onyia, Bone Metabolism Research Group, 0403, Endocrine Division, Lilly Research Laboratories, Indianapolis, Indiana 46285. E-mail: jeo{at}lilly.com

PTH stimulates bone formation in animals and humans, and the expressions of a number of genes have been implicated in the mediation of this effect. To discover new bone factors that initiate and support this phenomenon we used differential display RT-PCR and screened for genes that are selectively expressed in osteoblast- enriched femoral metaphyseal primary spongiosa of young male rats after a single sc injection of human PTH-(1–38) (8 µg/100 g). We show that one of the messenger RNAs that is up-regulated in bone is ADAMTS-1, a new member of the ADAM (A disintegrin and metalloprotease) gene family containing thrombospondin type I motifs. ADAMTS-1 consists of multiple domains common to ADAM family of proteins, including pro-, metalloprotease-like, and disintegrin-like domains. However, unlike other ADAMs, ADAMTS-1 does not possess a transmembrane or cytoplasmic domain and is a secreted protein. Northern blot analysis confirmed that ADAMTS-1 was up-regulated in both metaphyseal (14- to 35-fold) and diaphyseal (4.2-fold) bone 1 h after PTH-(1–38) injection and returned to control levels by 24 h. We also analyzed the regulation of ADAMTS-1 in response to various PTH/PTH-related peptide (PTHrP) analogs and found that PTH-(1–31) and PTHrP-(1–34), which activate the protein kinase A (PKA) pathway, induce ADAMTS-1 expression 1 h after injection, whereas PTH-(3–34) and PTH-(7–34), which do not activate the PKA pathway, did not regulate expression. To investigate the effect of other osteotropic agents, we analyzed ADAMTS-1 expression after a single dose of PGE₂ (6 mg/kg) and found that it was up-regulated 1 h after injection and returned to control levels by 6 h. In vitro ADAMTS-1 is expressed in primary osteoblasts and osteoblastic cell lines, but was not detectable in osteoclasts generated from macrophage colony-stimulating factor/receptor activator of NF-B ligand/transforming growth factor-ß1-treated bone marrow cells. Treatment of UMR 106 osteosarcoma cells with PTH, PGE₂, forskolin, or (Bu)₂cAMP increased ADAMTS-1 expression 7-, 4-, 5-, and 5-fold, respectively. Also, in vitro treatment with 1,25-dihydroxyvitamin D₃ increased ADAMTS-1 expression 3-fold. Tissue distribution analysis showed that ADAMTS-1 is expressed at high levels in many tissues, including the heart, lung, liver, skeletal muscle, and kidney. Taken together, these results demonstrate that ADAMTS-1 is specifically up-regulated in bone and osteoblasts by the osteotropic agents PTH, PTHrP, and PGE₂ possibly via the cAMP/PKA pathway. We speculate that the rapid and transient increase in ADAMTS-1 expression may contribute to some of the effects of PTH on bone turnover.

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