INTERMITTENT ADMINISTRATION OF PARATHYROID-HORMONE (1-34) STIMULATES MATRIX-METALLOPROTEINASE-9 (MMP-9) EXPRESSION IN RAT LONG-BONE

Intermittent doses of parathyroid hormone (PTH) stimulate bone formati on in animals and humans, but the molecular mechanisms underlying this phenomenon are not understood. Bone formation culminates with the exp ression of type I collagen, osteocalcin, and alkaline phosphatase, but genes that initiate and support the anabolic response are not known. To identify novel PTH-regulated genes in bone during the anabolic resp onse, we used differential display-polymerase chain reaction (DDRT-PCR ) to analyze RNA from young male rats injected with either human PTH ( 1-34) or vehicle control, once daily for 5 days. Total RNA was isolate d from the distal femur metaphysis at 1, 6, and 48 h after the final i njection and subjected to DDRT-PCR. We identified three PTH-responsive transcripts as matrix metalloproteinase-9 (MMP-9), creatine kinase, a nd the alpha 1(1) polypeptide chain (COL1A1) of type I collagen. The c oncomitant upregulation of MMP-9 and COL1A1 during bone formation was particularly intriguing. Further characterization of MMP-9 expression revealed that it was localized to osteoblasts, osteocytes, megakaryocy tes, and cells of the bone marrow in the rat distal femur metaphysis. Northern analysis for MMP-9 expression in other tissues indicated that this transcript was present in the kidney and brain. In vitro, PTH re gulated the protein synthesis of MMP-9 by osteoblasts of the primary s pongiosa. We propose that PTH may promote bone formation by mediating the subtle variation in MMP activities, thus preparing the extracellul ar matrix for the subsequent bone cell migration and deposition of new osteoid. J. Cell. Biochem. 70:391-401, 1998. (C) 1998 Wiley-Liss, Inc .