No abstract

We showed previously that some actions of prostaglandin E(2) (PGE(2)) on bone are caused by its degradation product, PGA(2), which mediates its effects via a class of nuclear receptors known as the peroxisome proliferator activator receptors (PPARs), suggesting that the PPARs may be involved in the regulation of bone formation. The aims of this study were to determine the effects of PPARalpha/delta agonists on bone in vitro and in vivo. PPAR agonists were examined in vitro using the fibroblastic colony-forming unit (CFU-f) assay. The PPARalpha/delta agonists linoleic acid (LA) and bezafibrate (Bez) were then administered to intact male rats by daily s.c. injection for 12 weeks with either vehicle (10% dimethyl sulfoxide), LA (0.3 mg/kg), or Bez (1 mg/kg). CFU-f assays were performed on stromal cells ex vivo. Bone mineral density (BMD) and serum markers of formation and resorption were measured. Bone histomorphometry was performed at cancellous and cortical bone sites. PPARalpha/delta agonists increased significantly the number of osteoblastic colonies as demonstrated by increased alkaline phosphatase activity, collagen production, and calcification. This increase was typically equal to or greater than that achieved with the known bone anabolic agent PGE(2). In intact male rats, LA and Bez increased metaphyseal BMD by 7% and 11%, respectively. Increased BMD was associated with an increase in total bone area, although no changes were observed in bone formation rate within the trabecular compartment. Serum osteocalcin and osteoprogenitor numbers were increased, whereas there was no change in either tartrate-resistant acid phosphatase 5b or osteoclast number. Both LA and Bez increased cortical bone area by approximately 38%, periosteal perimeter by 15%, and periosteal bone formation by 221% and 140%, respectively. There was no effect on medullary cavity area or endocortical perimeter. These data suggest that PPARalpha/delta may have roles in bone anabolism, specifically in the regulation of periosteal bone formation. They are potential therapeutic targets for osteoporosis therapy.

BACKGROUND The family of matrix metalloproteinases (MMPs) has been shown to be involved in proteolytic degradation of the extracellular matrix, which is an essential step in tumor invasion and metastasis. MMPs are tightly regulated by the levels of active enzymes and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). MMP‐2 and its ratio to TIMP‐2 have been associated with tumor recurrence and progression in a number of human malignancies. METHODS We examined the relationship between MMP‐2 and TIMP‐2 mRNA expression in 42 men with malignant (n = 32) and benign (n = 10) prostates using nonisotopic in situ hybridization and Northern blot analysis. RESULTS mRNA for MMP‐2 and TIMP‐2 was localized to the malignant epithelial cells of both high‐ and low‐grade tumors in the periphery of the glands and in areas of extracapsular involvement, and to the glandular epithelium in the benign prostates. Using Northern blot analysis, the mean MMP‐2 to TIMP‐2 ratio was approximately one in the benign prostates and low‐grade and ‐stage cancers. The MMP‐2 to TIMP‐2 ratio increased to 3.3 in the high‐grade and 2.8 in the high‐stage tumors. CONCLUSIONS The results suggest a close association between MMP‐2/TIMP‐2 expression and local tumor invasion, with a disruption in expression of the two genes leading to disease progression. Future studies should focus on the activity of these enzymes and on the ratio of enzyme/inhibitor expression, which may become a useful prognostic marker in prostate cancer. Prostate 42:18–25, 2000. © 2000 Wiley‐Liss, Inc.