Role of paraoxonase-1 in bone anabolic effects of parathyroid hormone in hyperlipidemic mice

Hyperlipidemia blunts anabolic effects of intermittent parathyroid hormone (PTH) on cortical bone, and the responsiveness to PTH are restored in part by oral administration of the antioxidant ApoA-I mimetic peptide, D-4F. To evaluate the mechanism of this rescue, hyperlipidemic mice overexpressing the high-density lipoprotein-associated antioxidant enzyme, paraoxonase 1 (Ldlr−/−PON1tg) were generated, and daily PTH injections were administered to Ldlr−/−PON1tg and to littermate Ldlr−/− mice. Expression of bone regulatory genes was determined by realtime RT-qPCR, and cortical bone parameters of the femoral bones by micro-computed tomographic analyses. PTH-treated Ldlr−/−PON1tg mice had significantly greater expression of PTH receptor (PTH1R), activating transcription factor-4 (ATF4), and osteoprotegerin (OPG) in femoral cortical bone, as well as significantly greater cortical bone mineral content, thickness, and area in femoral diaphyses compared with untreated Ldlr−/−PON1tg mice. In contrast, in control mice (Ldlr−/−) without PON1 overexpression, PTH treatment did not induce these markers. Calvarial bone of PTH-treated Ldlr−/−PON1tg mice also had significantly greater expression of osteoblastic differentiation marker genes as well as BMP-2-target and Wnt-target genes. Untreated Ldlr−/−PON1tg mice had significantly greater expression of PTHR1 than untreated Ldlr−/− mice, whereas sclerostin expression was reduced. In femoral cortical bones, expression levels of transcription factors, FoxO1 and ATF4, were also elevated in the untreated, control Ldlr−/−PON1tg mice, suggesting enhancement of cellular protection against oxidants. These findings suggest that PON1 restores responsiveness to PTH through effects on oxidant stress, PTH receptor expression, and/or Wnt signaling.

► Anabolic effects of PTH were tested in hyperlipidemic mice overexpressing PON1.
► Expression of antioxidant regulatory genes was induced in PON1 overexpression.
► Bone resorptive activity was reduced in PON1 overexpressing hyperlipidemic mice.
► PON1 restored responsiveness to intermittent PTH in bones of hyperlipidemic mice.