LPAR2 Regulates LPA-Induced Osteoclast Sealing Zone Dynamics
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Date
2010-06
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The Ohio State University
Abstract
Bone metastasis is an excruciating consequence of multiple primary cancers, and is commonly treated with bisphosphonate drugs. Osteoclasts, bone-resorbing cells vital to proper bone remodeling and fracture healing, are responsible for the formation of osteolytic bone tumors. Osteoclasts function through an actin-based structure called the actin sealing zone, or actin ring. Actin ring formation is required for proper bone resorption, and can be used to measure osteoclast function.
The Lee lab is investigating the mechanisms of lysophosphatidic acid (LPA) treatment on osteoclasts. LPA is a lipid molecule found at elevated levels in the blood of cancer patients. In preliminary in vitro experiments, osteoclasts were directly treated with LPA. Cells were also exposed to LPA in the presence of a common bisphosphonate, Zometa, which is currently used to treat the osteoporosis commonly observed in cancer patients. In the absence of Zometa, LPA increases the actin ring circumference and the number of cellular nuclei. Zometa treatment decreases the actin ring perimeter and number of nuclei. Osteoclasts treated with Zometa and LPA simultaneously show an expanded actin ring and elevated number of nuclei, similar to the phenotype induced by exposure to LPA alone. Cells treated with Zometa after LPA exposure showed no observable response to the drug.
LPA works through five known receptors, three of which are defined in osteoclasts. The LPA receptor (LPAR) 1/3 inhibitor Ki16425 did not suppress the actin ring increase by LPA. However, LPAR2 agonist FAP12 demonstrated effects identical to those observed in the presence of LPA on bone. Such data suggests that LPAR2 is responsible for the actin ring perimeter and nuclear quantity changes seen with LPA treatment. Small interfering RNAs (siRNAs) specific to LPAR2 were utilized to examine LPAR2 function. Knockdown of LPAR2 inhibited the actin ring expansion observed in cells with functional LPAR2. The results suggest that LPAR2 is a key element in LPA-induced actin sealing zone dynamics, and is consequently a new target for alternative drug therapies to treat LPA-induced bone metastasis.
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Keywords
Osteoclasts, LPA, Cancer, Bisphosphonate