Lrp4 in osteoblasts suppresses bone formation and promotes osteoclastogenesis and bone resorption

Abstract

Bone mass is maintained by balanced activity of osteoblasts and osteoclasts. Lrp4 (low-density lipoprotein receptor related protein 4) is a member of the LDL receptor family, whose mutations have been identified in patients with high-bone-mass disorders, such as sclerosteosis and van Buchem diseases. However, it remains unknown whether and how Lrp4 regulates bone-mass homeostasis in vivo. Here we provide evidence that Lrp4-null mutation or specific mutation in osteoblast-lineage cells increased cortical and trabecular bone mass, which was associated with elevated bone formation and impaired bone resorption. This phenotype was not observed in osteoclast-selective Lrp4 knockout mice. Mechanistic studies indicate that loss of Lrp4 function in osteoblast-lineage cells increased serum levels of sclerostin, a key factor for bone-mass homeostasis that interacts with Lrp4, but abolished the inhibition of Wnt/β-catenin signaling and osteoblastic differentiation by sclerostin. Concomitantly, sclerostin induction of RANKL (receptor activator of nuclear kappa B ligand) was impaired, leading to a lower ratio of RANKL over OPG (osteoprotegerin) (a key factor for osteoclastogenesis). Taken together, these results support the view for Lrp4 as a receptor of sclerostin to inhibit Wnt/β-catenin signaling and bone formation and identify Lrp4 as a critical player in bonemass homeostasis.one remodeling is a dynamic process essential for maintenance of skeletal integrity and bone homeostasis (1). Bone mass is tightly regulated by bone-forming osteoblasts (OBs) and bone-resorbing osteoclasts (OCs). OBs are differentiated from bone marrow stromal cells (BMSCs) or mesenchymal progenitor cells, whereas OCs are derived from hematopoietic bone marrow macrophages or myeloid monocytes (BMMs). The balance of bone formation and resorption is critical for maintenance of healthy bone mass. The imbalance of bone formation and resorption could result in high-bone-mass disorders such as sclerosteosis and van Buchem disease or bone loss such as osteoporosis.The canonical Wnt/β-catenin signaling is critical to regulate bone-mass homeostasis (1, 2). Binding of Wnt ligands to a dualreceptor complex of frizzled and Lrp5/6 leads to accumulation of cytoplasmic β-catenin and translocation of β-catenin into the nucleus to regulate gene expression. This pathway is required for commitment of mesenchymal stem cells to the OB lineage, OB precursor cell proliferation and differentiation, and OC genesis and activation (1-3). Clinically, Lrp5 mutations are associated with the osteoporosis-pseudoglioma syndrome, a low-bone-mass disorder (4), as well as with high-bone-mass disorders (5, 6).Lrp4 is a member of LDL family protein, containing a large extracellular region with multiple LDLa, EGF-like, and β-propeller repeats, a transmembrane domain, and a short C-terminal region. Lrp4 is a receptor of agrin (7,8), critical for neuromuscular junction formation. Mice lacking Lrp4 (null allele) die at birth because of inability to breathe (9). Lrp4 is also highly related to...

Multifarious effects of 17-β-estradiol on apolipoprotein E receptors gene expression during osteoblast differentiation <i>in vitro </i>

“…LRP4 is a novel receptor binding to osteoblast expressed dickkopf-1 (Dkk1) and sclerostin, plays a physiological role in the regulation of bone growth and turnover likely through Wnt and BMP signaling pathways (28,62). Apoer2 has been shown as a positive factor of the canonical Wnt signaling pathway, increasing Wnt-induced transcriptional responses, promoting Wnt-induced β-catenin accumulation, and controlling osteoblast differentiation (32).…”

“…ApoE has a strong affinity for and is the main ligand for members of the LDLR family. The LDLR family is a highly conserved receptor family with diverse functions in cellular physiology (shown in Table 1) (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). LDLR is the prototype of the entire family, and members of this family are structurally and functionally related to it.…”

Multiple modes of Lrp4 function in modulation of Wnt/β-catenin signaling during tooth development

“…In postnatal bone, loss of Lrp4 in osteoblasts leads to increased bone mass reminiscent of bone phenotypes observed in mice deficient for Sost (Chang et al, 2014a;Collette et al, 2012;Li et al, 2008;Xiong et al, 2015). Human patients with the LRP4 mutation R1170W display bone overgrowth and the mutation results in reduced binding to SOST and abolishes the LRP4 function as a facilitator of SOST in cultured cells (Leupin et al, 2011).…”

Low-density lipoprotein receptor deficiency impaired mice osteoblastogenesis <i>in vitro </i>

“…LRP5/LRP6 affected osteoblastogenesis by inducing the Wnt signal as co-receptor in the dual receptor complex with frizzled (FZD) (32). LRP4, the third member of the LRP5 and LRP6 subfamily of LDLRs, inhibited the Wnt signaling pathway by facilitating sclerostin action, the antagonist of Wnt signaling pathway (29,36). Dimerization of LRP6 through its LDLR domain induced canonical Wnt pathway activation (47).…”

“…For example, human osteoblasts expressed low-density lipoprotein receptorrelated protein (LRP) 1 with a capacity for osteocalcin carboxylation (28). LRP4, LRP5/6, and LRP8 were involved in the maintenance of bone (29)(30)(31)(32)(33)(34)(35)(36). However, the role of LDLR in bone metabolism was unclear with controversial results in recent studies.…”