Endogenous parathyroid hormone-related protein compensates for the absence of parathyroid hormone in promoting bone accrual in vivo in a model of bone marrow ablation

Abstract

To assess the effect of hypoparathyroidism on osteogenesis and bone turnover in vivo, bone marrow ablation (BMXs) were performed in tibias of 8-week-old wild-type and parathyroid hormone-null (PTH-/-) mice and newly formed bone tissue was analyzed from 5 days to 3 weeks after BMX. At 1 week after BMX, trabecular bone volume, osteoblast numbers, alkaline phosphatase-positive areas, type I collagen-positive areas, PTH receptor-positive areas, calcium sensing receptor-positive areas, and expression of bone formation-related genes were all decreased significantly in the diaphyseal regions of bones of PTH-/- mice compared to wild-type mice. In contrast, by 2 weeks after BMX, all parameters related to osteoblastic bone accrual were increased significantly in PTH-/- mice. At 5 days after BMX, active tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts had appeared in wild-type mice but were undetectable in PTH -/- mice, Both the ratio of mRNA levels of receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) and TRAP-positive osteoclast surface were still reduced in PTH-/- mice at 1 week but were increased by 2 weeks after BMX. The expression levels of parathyroid hormone-related protein (PTHrP) at both mRNA and protein levels were upregulated significantly at 1 week and more dramatically at 2 weeks after BMX in PTH -/- mice. To determine whether the increased newly formed bones in PTH-/- mice at 2 weeks after BMX resulted from the compensatory action of PTHrP, PTH-/-PTHrP+/- mice were generated and newly formed bone tissue was compared in these mice with PTH-/- and wild-type mice at 2 weeks after BMX. All parameters related to osteoblastic bone formation and osteoclastic bone resorption were reduced significantly in PTH-/-PTHrP+/- mice compared to PTH-/- mice. These results demonstrate that PTH deficiency itself impairs osteogenesis, osteoclastogenesis, and osteoclastic bone resorption, whereas subsequent upregulation of PTHrP in osteogenic cells compensates by increasing bone accrual. © 2013 American Society for Bone and Mineral Research © 2013 American Society for Bone and Mineral Research.