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LRP4: A new bone anabolic drug target?

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Most available therapies for osteoporosis function as inhibitors of bone resorption. However, in patients with very low bone mass or those who already have a fragility fracture, anabolic therapies, which enhance bone formation, may be more effective (1). Currently, only analogs of parathyroid hormone are approved as bone anabolic agents to treat osteoporosis. The discovery that the canonical Wnt beta-catenin signaling pathway stimulates bone formation has identified a number of new drug targets, which may be exploited to develop novel anabolic therapies for osteoporosis (2). Wnts are signaling proteins that are produced in the bone microenvironment. They bind specific receptor complexes on osteoblast lineage cells and enhance the development and function of mature osteoblasts. The receptors for canonical Wnts include the protein frizzled and its co-receptors, which are either low-density lipoprotein-related proteins (LRP) 5 or 6 (3). There are a large number of Wnt proteins that function as ligands for the canonical Wnt signaling pathway. In addition, there are inhibitors of Wnt signaling that are produced in bone and modulate the effect of Wnt proteins. Among these are sclerostin and dickkopf-related protein 1 (DKK-1). Both bind LRP 5/6 and prevent canonical Wnts from interacting with their cognate receptor complex.


Much attention has focused on the potential of antibodies to sclerostin to act as a bone anabolic therapy (4). By binding specifically to sclerostin, these antibodies prevent sclerostin from binding to frizzled-LRP5/6 receptors and enhance bone mass. A phase two clinical trial demonstrated that an anti-sclerostin antibody had a significant anabolic effect on bone mass in humans (5). However, the mechanisms by which sclerostin inhibits osteoblast development and function is incompletely understood.


In 2011 Leupin et al demonstrated that LRP4 is also involved in the ability of sclerostin to inhibit osteoblasts (6). These authors screened proteins that directly bound sclerostin. They identified LRP 4 as a sclerostin-binding protein, which facilitated the ability of sclerostin to inhibit canonical Wnt signaling. They also examined two patients with sclerosteosis, which is typically caused by a deficiency in sclerostin production and is characterized by an abnormally high bone mass. Significantly, they discovered that their patients actually had mutations in their LRP4 gene, which prevented the binding of mutant LRP 4 to sclerostin (6).


In a recent follow up paper this group examined mice with conditional deletions of LRP 4 either in both osteoblasts and osteocytes or just in osteocytes (7). They found that, like patients with LRP 4 mutations and sclerosteosis, both LRP 4 conditionally deleted mouse models had increased bone mass and rates of bone formation. Most importantly, the authors also developed antibodies that specifically targeted the region of LRP 4, which bound sclerostin. Antibody binding occurred without affecting the interaction of LRP 4 with agrin and muscle-specific kinase, which is important for neuromuscular junction signaling. When injected into rats, these antibodies stimulated bone mass and increased bone formation rates. Hence, they show promise as a novel bone anabolic therapy.


These authors also found that both conditional deletion of LRP 4 in mice and the prevention of LRP 4 binding to sclerostin with anti-LRP 4 antibodies in rats markedly increased serum sclerostin levels. Furthermore, neither model was associated with increased levels of sclerostin mRNA in bone. These results suggest that LRP 4 acts as a binding protein, which maintains sclerostin in the bone microenvironment. In the absence of sclerostin-LRP 4 interactions, much more sclerostin is free to circulate in serum. Hence, measuring serum sclerostin may be a poor surrogate for evaluating the local production of sclerostin in bone and the rate of bone formation. In situations in which bone LRP 4 levels change, serum sclerostin levels may vary without an alteration in sclerostin production in bone.


Whether these results translate into a new therapeutic option for patients with osteoporosis remains to be seen. However, they are intriguing and provide new insights into how canonical Wnt signaling pathways regulates bone mass.


Joe Lorenzo

Farmington, Connecticut, USA

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