ADAMTS-1: A cellular disintegrin and metalloprotease with thrombospondin motifs is a target for parathyroid hormone in bone

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 use d differential display RT-PCR and screened for genes that are selectively e xpressed in osteoblast-enriched femoral metaphyseal primary spongiosa of yo ung male rats after a single sc injection of human PTH-(1-38) (8 mug/100 g) . We show that one of the messenger RNAs that is up-regulated in bone is AD AMTS-1, a new member of the ADAM (A disintegrin and metalloprotease) gene f amily containing thrombospondin type I motifs. ADAMTS-1 consists of multipl e domains common to ADAM family of proteins, including pro-, metalloproteas e-like, and disintegrin-like domains. However, unlike other ADAMs, ADAMTS-1 does not possess a transmembrane or cytoplasmic domain and is a secreted p rotein. 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 analyz ed the regulation of ADAMTS-1 in response to various PTH/PTH-related peptid e (PTHrP) analogs and found that PTH-(1-31) and PTHrP-(1-34), which activat e 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 o steotropic agents, we analyzed ADAMTS-1 expression after a single dose of P GE, (6 mg/kg) and found that it was up-regulated 1 h after injection and re turned to control levels by 6 h. In vitro ADAMTS-1 is expressed in primary osteoblasts and osteoblastic cell lines, but was not detectable in osteocla sts generated from macrophage colony-stimulating factor/receptor activator of NF-kappaB ligand/transforming growth factor beta1-treated bone marrow ce lls. Treatment of UMR 106 osteosarcoma cells with PTH, PGE(2), forskolin, o r (Bu)(2)cAMP increased ADAMTS-1 expression 7-, 4-, 5-, and 5-fold, respect ively. Also, in vitro treatment with 1 alpha ,25-dihydroxyvitamin D-3 incre ased ADAMTS-1 expression 8-fold. Tissue distribution analysis showed that A DAMTS-1 is expressed at high levels in many tissues, including the heart, l ung, liver, skeletal muscle, and kidney. Taken together, these results demo nstrate that ADAMTS-1 is specifically up-regulated in bone and osteoblasts by the osteotropic agents PTH, PTHrP, and PGE, possibly via the cAMP/PKA pa thway. We speculate that the rapid and transient increase in ADAMTS-1 expre ssion may contribute to some of the effects of PTH on bone turnover.