title: Accentuated osteoclastic response to parathyroid hormone undermines bone mass acquisition in osteonectin-null mice.
abstract: Matricellular proteins play a unique role in the skeleton as regulators of bone remodeling, and the matricellular protein osteonectin (SPARC, BM-40) is the most abundant non-collagenous protein in bone. In the absence of osteonectin, mice develop progressive low turnover osteopenia, particularly affecting trabecular bone. Polymorphisms in a regulatory region of the osteonectin gene are associated with bone mass in a subset of idiopathic osteoporosis patients, and these polymorphisms likely regulate osteonectin expression. Thus it is important to determine how osteonectin gene dosage affects skeletal function. Moreover, intermittent administration of parathyroid hormone (PTH) (1-34) is the only anabolic therapy approved for the treatment of osteoporosis, and it is critical to understand how modulators of bone remodeling, such as osteonectin, affect skeletal response to anabolic agents. In this study, 10 week old female wild type, osteonectin-haploinsufficient, and osteonectin-null mice (C57Bl/6 genetic background) were given 80 microg/kg body weight/day PTH(1-34) for 4 weeks. Osteonectin gene dosage had a profound effect on bone microarchitecture. The connectivity density of trabecular bone in osteonectin-haploinsufficient mice was substantially decreased compared with that of wild type mice, suggesting compromised mechanical properties. Whereas mice of each genotype had a similar osteoblastic response to PTH treatment, the osteoclastic response was accentuated in osteonectin-haploinsufficient and osteonectin-null mice. Eroded surface and osteoclast number were significantly higher in PTH-treated osteonectin-null mice, as was endosteal area. In vitro studies confirmed that PTH induced the formation of more osteoclast-like cells in marrow from osteonectin-null mice compared with wild type. PTH treated osteonectin-null bone marrow cells expressed more RANKL mRNA compared with wild type. However, the ratio of RANKL:OPG mRNA was somewhat lower in PTH treated osteonectin-null cultures. Increased expression of RANKL in response to PTH could contribute to the accentuated osteoclastic response in osteonectin-/- mice, but other mechanisms are also likely to be involved. The molecular mechanisms by which PTH elicits bone anabolic vs. bone catabolic effects remain poorly understood. Our results imply that osteonectin levels may play a role in modulating the balance of bone formation and resorption in response to PTH.
authors.affiliation: University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Luciene
authors.initials: L
authors.lastname: Machado do Reis
authors.affiliation: University of Connecticut Heath Center, Farmington, CT, USA.
authors.forename: Catherine B
authors.initials: CB
authors.lastname: Kessler
authors.affiliation: University of Connecticut Heath Center, Farmington, CT, USA.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Adams
authors.affiliation: University of Connecticut Heath Center, Farmington, CT, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Lorenzo
authors.affiliation: University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Vanda
authors.initials: V
authors.lastname: Jorgetti
authors.affiliation: University of Connecticut Heath Center, Farmington, CT, USA. Electronic address: adelany@uchc.edu.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Delany
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D001842:Bone and Bones / Q000187:drug effects* / Q000473:pathology*; D005260:Female; D005269:Femur / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D015676:Osteonectin / Q000172:deficiency* / Q000378:metabolism; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D010281:Parathyroid Hormone / Q000494:pharmacology*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013131:Spine / Q000187:drug effects; D014057:Tomography, X-Ray Computed
chemical_list: D015676:Osteonectin; D053244:Osteoprotegerin; C470125:PTH protein, human; D010281:Parathyroid Hormone; D053245:RANK Ligand; D012333:RNA, Messenger