15-Deoxy-Δ12,14-Prostaglandin J2 Inhibits Osteolytic Breast Cancer Bone Metastasis and Estrogen Deficiency-Induced Bone Loss

Abstract

Breast cancer is the major cause of cancer death in women worldwide. The most common site of metastasis is bone. Bone metastases obstruct the normal bone remodeling process and aberrantly enhance osteoclast-mediated bone resorption, which results in osteolytic lesions. 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is an endogenous ligand of peroxisome proliferator-activated receptor gamma (PPARγ) that has anti-inflammatory and antitumor activity at micromolar concentrations through PPARγ-dependent and/or PPARγ-independent pathways. We investigated the inhibitory activity of 15d-PGJ2 on the bone loss that is associated with breast cancer bone metastasis and estrogen deficiency caused by cancer treatment. 15d-PGJ2 dose-dependently inhibited viability, migration, invasion, and parathyroid hormone-related protein (PTHrP) production in MDA-MB-231 breast cancer cells. 15d-PGJ2 suppressed receptor activator of nuclear factor kappa-B ligand (RANKL) mRNA levels and normalized osteoprotegerin (OPG) mRNA levels in hFOB1.19 osteoblastic cells treated with culture medium from MDA-MB-231 cells or PTHrP, which decreased the RANKL/OPG ratio. 15d-PGJ2 blocked RANKL-induced osteoclastogenesis and inhibited the formation of resorption pits by decreasing the activities of cathepsin K and matrix metalloproteinases, which are secreted by mature osteoclasts. 15d-PGJ2 exerted its effects on breast cancer and bone cells via PPARγ-independent pathways. In Balb/c nu/nu mice that received an intracardiac injection of MDA-MB-231 cells, subcutaneously injected 15d-PGJ2 substantially decreased metastatic progression, cancer cell-mediated bone destruction in femora, tibiae, and mandibles, and serum PTHrP levels. 15d-PGJ2 prevented the destruction of femoral trabecular structures in estrogen-deprived ICR mice as measured by bone morphometric parameters and serum biochemical data. Therefore, 15d-PGJ2 may be beneficial for the prevention and treatment of breast cancer-associated bone diseases.

Peroxisome proliferator‐activated receptor γ plays dual roles on experimental periodontitis in rats

“…To understand the effect of PPARγ on alveolar bone remodelling during the periodontitis progression, we detected bone metabolism‐related factors by ELISA and immunohistochemistry and investigated the loss of alveolar bone by several methods. Using RGZ to activate PPARγ for 4 weeks, promoted the expression of ALP and BMP‐2, and reduced the RANKL/OPG ratio in serum, which were consistent with the findings in previous studies (Kim et al., ; Koufany et al., ). Nevertheless, after 8 weeks the results reversed with the decreased expression of ALP, BMP‐2 and the increased RANKL/OPG ratio with RGZ intervention.…”

Renin inhibitor aliskiren exerts beneficial effect on trabecular bone by regulating skeletal renin-angiotensin system and kallikrein-kinin system in ovariectomized mice

“…The OVX mice after treatment with aliskiren in this study displayed the decreased bone resorption as demonstrated by the reduced excretion of urinary calcium and the decreased level of serum TRAP; moreover, aliskiren could markedly reduce the TRAPpositive osteoclasts number in trabecular bone and downregulate the expression of osteoclast-specific genes, including carbonic anhydrase II (CAII), matrix metalloproteinase (MMP)-9, and Cathepsin K. MMP-9 is the enzyme secreted from the ruffled border of osteoclasts to dissolve the organic components of bone, and CAII in osteoclasts is responsible for dissolving the bone inorganic substance [29]. Cathepsin K, one of proteolytic enzymes, degrades organic components in the bone matrix [46]. Therefore, the present study revealed that the inhibition of aliskiren on bone resorption via suppressing the osteoclastogenesis and the osteoclastic resorptive activity might be the potential mechanism for the beneficial effects of aliskiren on trabecular bone of OVX mice.…”

Artemisinin-Daumone Hybrid Inhibits Cancer Cell-Mediated Osteolysis by Targeting Cancer Cells and Osteoclasts

“…After 24 h, each wound area was photographed. The width of the wound area was measured using ImageJ software, and the percentage of wound closure was derived by using the following formula as previously described: [1 -(final wound width/initial wound width)] x 100 [26].…”

“…Clear zones against the blue background indicate the gelatinolytic activity of MMPs. Cathepsin K levels in the culture media were determined using a SensiZyme cathepsin K activity assay kit (Sigma-Aldrich) according to the manufacturer's instructions [26].…”