Lysophosphatidic Acid Elevates Cytosolic Calcium and Enhances Osteoclast Survival

Objective:  Lysophosphatidic acid (LPA) is a bioactive phospholipid that acts through a family of receptors that couple to multiple G proteins.  Activated platelets are a source of LPA and we have recently shown that osteoblasts also produce LPA, raising the possibility that LPA may mediate local signaling in bone between osteoblasts and osteoclasts.  However, nothing is known about possible actions of LPA on osteoclasts.  The aim of this study was to investigate the responses of osteoclasts to LPA.

Methods:  Osteoclasts were isolated from the long bones of neonatal rats.  Cytosolic free calcium concentration was measured using fura-2.  Cell counting and assessment of nuclear morphology were used to quantify osteoclast survival and apoptosis.

Results:  Focal application of LPA elicited an acute, transient increase in cytosolic calcium. This response was concentration-dependent, with half maximal effects observed at 3 µM LPA, and was blocked by the LPA receptor antagonist VPC-32183.  LPA enhanced survival of rat osteoclasts over a period of 18 hours (survival increased from 18 ± 1% in vehicle-treated cultures to 35 ± 2% in cultures treated with 5 µM LPA, mean ± SEM, P < 0.001).  This effect was also blocked by VPC-32183.  Consistent with its effects on survival, LPA suppressed apoptosis at 6 hours.

Conclusion:  This study reveals for the first time that osteoclasts respond directly to LPA with elevation of cytosolic calcium.  Moreover, LPA reduces osteoclast apoptosis and enhances survival.  Thus, LPA may mediate intercellular signaling between osteoblasts and osteoclasts, a novel signaling axis promoting bone resorption.

This research is supported by the Canadian Institutes of Health Research (CIHR).