Proteoglycan 4: A dynamic regulator of skeletogenesis and parathyroid hormone skeletal anabolism

• Published in: Journal of bone and mineral research Vol. 27; no. 1; pp. 11 - 25
• Main Authors: Novince, Chad M, Michalski, Megan N, Koh, Amy J, Sinder, Benjamin P, Entezami, Payam, Eber, Matthew R, Pettway, Glenda J, Rosol, Thomas J, Wronski, Thomas J, Kozloff, Ken M, McCauley, Laurie K
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.01.2012; Wiley; Wiley Subscription Services, Inc
• Subjects: Animals; Biological and medical sciences; Biomarkers - metabolism; bone; Bone and Bones - anatomy & histology; Bone and Bones - diagnostic imaging; Bone and Bones - drug effects; Bone and Bones - metabolism; Bone Remodeling - drug effects; Femur - anatomy & histology; Femur - diagnostic imaging; Femur - drug effects; Femur - metabolism; FGF-2; Fibroblast Growth Factor 2 - blood; Fibroblast Growth Factor 2 - genetics; Fibroblast Growth Factor 2 - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Growth Plate - drug effects; Growth Plate - metabolism; Humans; Insulin-Like Growth Factor I - metabolism; Joints - drug effects; Joints - physiology; liver; Liver - drug effects; Liver - metabolism; Mesenchymal Stem Cells - drug effects; Mesenchymal Stem Cells - metabolism; Mice; Mice, Inbred C57BL; Organ Size - drug effects; Osteogenesis - drug effects; Osteogenesis - genetics; Parathyroid Hormone - pharmacology; Prg4; Proteoglycans - deficiency; Proteoglycans - genetics; Proteoglycans - metabolism; PTH; Range of Motion, Articular - drug effects; RNA, Messenger - genetics; RNA, Messenger - metabolism; Skeleton and joints; Tibia - anatomy & histology; Tibia - drug effects; Tibia - growth & development; Tibia - metabolism; Vertebrates: osteoarticular system, musculoskeletal system; X-Ray Microtomography; Proteoglycan; Digestive system; PTH; Liver; Peptide hormone; Basic fibroblast growth factor; PRG4; Osteoarticular system; FGF-2; Vertebrata; Mammalia; Parathyroid hormone; Bone
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1002/jbmr.508

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. © 2012 American Society for Bone and Mineral Research