title: Proteoglycan 4: a dynamic regulator of skeletogenesis and parathyroid hormone skeletal anabolism.
abstract: Proteoglycan 4 (Prg4), known for its lubricating and protective actions in joints, is a strong candidate regulator of skeletal homeostasis and parathyroid hormone (PTH) anabolism. Prg4 is a PTH-responsive gene in bone and liver. Prg4 null mutant mice were used to investigate the impact of proteoglycan 4 on skeletal development, remodeling, and PTH anabolic actions. Young Prg4 mutant and wild-type mice were administered intermittent PTH(1-34) or vehicle daily from 4 to 21 days. Young Prg4 mutant mice had decreased growth plate hypertrophic zones, trabecular bone, and serum bone formation markers versus wild-type mice, but responded with a similar anabolic response to PTH. Adult Prg4 mutant and wild-type mice were administered intermittent PTH(1-34) or vehicle daily from 16 to 22 weeks. Adult Prg4 mutant mice had decreased trabecular and cortical bone, and blunted PTH-mediated increases in bone mass. Joint range of motion and animal mobility were lower in adult Prg4 mutant versus wild-type mice. Adult Prg4 mutant mice had decreased marrow and liver fibroblast growth factor 2 (FGF-2) mRNA and reduced serum FGF-2, which were normalized by PTH. A single dose of PTH decreased the PTH/PTHrP receptor (PPR), and increased Prg4 and FGF-2 to a similar extent in liver and bone. Proteoglycan 4 supports endochondral bone formation and the attainment of peak trabecular bone mass, and appears to support skeletal homeostasis indirectly by protecting joint function. Bone- and liver-derived FGF-2 likely regulate proteoglycan 4 actions supporting trabeculae formation. Blunted PTH anabolic responses in adult Prg4 mutant mice are associated with altered biomechanical impact secondary to joint failure.
authors.affiliation: Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Chad M
authors.initials: CM
authors.lastname: Novince
authors.forename: Megan N
authors.initials: MN
authors.lastname: Michalski
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Koh
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Sinder
authors.forename: Payam
authors.initials: P
authors.lastname: Entezami
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Eber
authors.forename: Glenda J
authors.initials: GJ
authors.lastname: Pettway
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rosol
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wronski
authors.forename: Ken M
authors.initials: KM
authors.lastname: Kozloff
authors.forename: Laurie K
authors.initials: LK
authors.lastname: McCauley
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016723:Bone Remodeling / Q000187:drug effects; D001842:Bone and Bones / Q000033:anatomy & histology / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism*; D005269:Femur / Q000033:anatomy & histology / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006132:Growth Plate / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007596:Joints / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects* / Q000235:genetics; D010281:Parathyroid Hormone / Q000494:pharmacology*; D011509:Proteoglycans / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016059:Range of Motion, Articular / Q000187:drug effects; D013977:Tibia / Q000033:anatomy & histology / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D055114:X-Ray Microtomography; D000099158:Proteoglycan 4
chemical_list: D015415:Biomarkers; D016222:Fibroblast Growth Factor 2; D007334:Insulin-Like Growth Factor I; D010281:Parathyroid Hormone; D011509:Proteoglycans; D012333:RNA, Messenger; C498837:Prg4 protein, mouse; D000099158:Proteoglycan 4