Low-density lipoprotein receptor–related protein 5 (LRP5) is a cell surface Frizzled co-receptor for Wnt proteins involved in activating the canonical Wnt/β-catenin signaling pathway.(1,2) Inactivation of LRP5 through nonsense, frameshift, and missense mutations results in osteoporosis pseudoglioma syndrome (OPPG),(3) a rare disease characterized by low bone mass and congenital or early-onset blindness. Disruption of the mouse Lrp5 gene results in similar skeletal and ocular phenotypes.(4,5) Another protein, LRP6, is believed to fulfill the functions of LRP5 in all nonskeletal, nonocular tissues.
The importance of LRP5 in determining bone mass is highlighted by the independent discovery by two groups that healthy subjects with extremely high bone mass have an activating G171V mutation in LRP5.(6,7) Subsequent work has identified additional activating mutations,(8) with all mutations described to-date located in the first of four extracellular WV “propeller” regions of LRP5. Transgenic mice expressing Lrp5 with this G171V mutation have similarly high bone mass.(9) In addition, genetic manipulation of proteins that modulate the canonical Wnt/β-catenin signaling pathway also modulate bone mass. Cells expressing the activating LRP5 mutation do not respond to the secreted Wnt antagonist dickkopf (DKK)-1,(6,10) and overexpression of DKK-1 by osteoblasts has been implicated in the bone loss observed in patients with multiple myeloma.(11) In addition to modulation by dickkopfs, Wnt signaling is inhibited by five secreted Frizzled related proteins (sFRPs)(12) and sclerostin.(13,14) Mice with disruption of the sFRP1 gene develop high bone mass after 6 months of age.(15) Humans(16) and mice(17) with disruptions in sclerostin have extremely high bone mass. Furthermore, mice harboring either gain-of function or loss-of-function mutations of β-catenin in osteoblasts exhibit high and low bone mass phenotypes, respectively.(18) Inhibiting glycogen synthase kinase-3β, a component of Wnt/β-catenin signaling, by treating mice with lithium increases bone mass.(19)
Lrp5 knockout (KO) mice have decreased osteoblast proliferation and bone matrix synthesis,(4) whereas increased osteoblast number and life span are observed in the Lrp5 G117V transgenic mice.(9) The osteopenia of Lrp5-deficient mice can be completely rescued when these animals are crossed with mice harboring a constitutively active allele of β-catenin in osteoblasts, supporting the hypothesis that Lrp5 signals through the canonical Wnt/β-catenin pathway.(20) Based on these observations, it would be anticipated that endogenous factors that regulate the expression of Lrp5 would have the potential to influence bone formation through this pathway. PTH has been shown to regulate the expression of components of the Wnt signaling pathway in cultured bone cells and in vivo,(21–23) suggesting that some of its actions on bone may involve Lrp5.
PTH is an important physiological regulator of mineral homeostasis and has bone anabolic and catabolic actions. When administered intermittently, PTH induces substantial increases in osteoblast surface, osteoid surface, and osteoid volume in animals, resulting in increased bone mass and strength.(24–27) In humans, clinical studies have shown that PTH increases bone mass and reduces vertebral and nonvertebral fractures.(28) Based on these findings, PTH was approved by the FDA for treatment of established osteoporosis.(29)
Whereas the skeletal benefits of intermittent PTH are well recognized, the molecular mechanisms underlying its anabolic actions on bone are not completely understood. The purpose of this study was to use Lrp5-deficient mice to evaluate the potential requirement for this gene in mediating PTH-induced bone formation.