title: 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.
authors.affiliation: The State Key Laboratory of Reproductive Medicine, The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhu
authors.forename: Xichao
authors.initials: X
authors.lastname: Zhou
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: David
authors.initials: D
authors.lastname: Goltzman
authors.forename: Andrew
authors.initials: A
authors.lastname: Karaplis
authors.forename: Dengshun
authors.initials: D
authors.lastname: Miao
mesh_terms: D055011:Ablation Techniques; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology* / Q000601:surgery*; D016723:Bone Remodeling; D001862:Bone Resorption / Q000235:genetics / Q000473:pathology; D001842:Bone and Bones / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D057895:Haploinsufficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis; D010281:Parathyroid Hormone / Q000172:deficiency* / Q000378:metabolism; D044162:Parathyroid Hormone-Related Protein / Q000172:deficiency / Q000378:metabolism*; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism; D044169:Receptors, Calcium-Sensing; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism
chemical_list: C577923:CASR protein, mouse; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D044168:Receptor, Parathyroid Hormone, Type 1; D044169:Receptors, Calcium-Sensing; D043562:Receptors, G-Protein-Coupled
keywords: BONE MARROW ABLATION; BONE TURNOVER; HYPOPARATHYROIDISM; OSTEOGENESIS; PTH; PTHRP