RESEARCH HIGHLIGHTS Nature Reviews Rheumatology 7, 373 (2011); published online 21 June 2011; doi:10.1038/nrrheum.2011.84 BONE Evidence for local effects of LRP5 on bone mass he question of how LRP5 (LDL Cui et al. found no effect of Lrp5 receptor-related protein 5) exerts its genotype on serotonin synthesis in the Teffects on bone formation has come gut. Activation of Lrp5 HBM alleles, under debate. New findings published by or inactivation of wild-type Lrp5, Cui et al. in Nature Medicine support a in serotonin-producing cells in the local role for LRP5 signaling in bone. duodenum did not affect bone mass. LRP5 was first implicated in the In addition, bone mass did not seem to regulation of bone mass through be affected by inhibition of tryptophan studies of two human genetic diseases: hydroxylase 1, the rate-limiting enzyme heterozygous missense mutations in LRP5 of peripheral serotonin synthesis, whether were shown to produce a dominantly induced genetically or pharmacologically. inherited high bone mass (HBM) The reasons for the discrepancy between phenotype, whereas loss-of-function the findings of this study and earlier LRP5 mutations were shown to cause work that led to the serotonin hypothesis osteoporosis-pseudoglioma syndrome are unknown, but could be related to (OPPG), which is associated with low differences in the mice studied or to other bone mass. “What excited the bone technical aspects of the research. research community was that LRP5 Although the data from Cui et al. does appeared to function in the Wnt signaling not support the model of Lrp5 expression Dreamstime pathway, which had previously not been | in the gut having a major influence on implicated in regulating bone strength,” bone mass, they do not exclude the says Matthew Warman, one of the authors possibility that Lrp5 could regulate bone © Rob3000 of the Nature Medicine paper. Data from mass indirectly through its function at other lines of investigation supported a other sites. Investigating this possibility, direct role for Wnt signaling in bone mass enabled them to compare the effect of the researchers conducted further tests accrual; however, direct proof that LRP5 inheriting Lrp5 HBM alleles with the that showed that selectively activating Lrp5 functioned locally in bone cells or that it effect of activating Lrp5 HBM alleles in HBM alleles in cells that form bone in was a transducer of Wnt signaling in bone specific cell types. “Perhaps the most the appendicular skeleton but not in cells cells was lacking. intriguing result from our present study is that form the bone in axial skeleton led to It has since been hypothezised that, that activating an Lrp5 HBM allele in the increased bone mass in the limbs but not surprisingly, LRP5 influences bone most mature bone cells, the osteocytes, in the vertebrae. formation not through its role as a Wnt appears as effective at increasing bone In summary, the data presented by co-receptor on osteoblasts, but indirectly, mass as inheriting the active Lrp5 HBM Cui et al. indicate that Lrp5 functions via its effects on the production of in all cells,” says Warman. In addition, to regulate bone mass in mice via Wnt serotonin (5-hydroxytryptophan) in the mice with conditional inactivation of signaling in osteocytes, thereby acting gut. Cui et al. sought to independently Lrp5 in osteocytes had decreased bone locally rather than via other sites. test this serotonin hypothesis and mass in comparison with their wild-type The researchers are now keen to also determine where and how LRP5 littermates. determine whether increasing the activity functioned to regulate bone mass. Together, the findings indicate that of LRP5 in older mice is as effective as it is Instead of confirming a serotonin-based bone mass is regulated by Lrp5 signaling in younger mice at increasing bone mass mechanisms, however, their data suggest in mature cells. “The importance of and strength. If this proves to be the case, that LRP5 functions locally in bone cells. this observation is that it might not be LRP5-targeted interventions might be The researchers were able to determine necessary to find therapies that target applicable to the treatment of age-related the site of Lrp5 function in mouse uncommitted cells to become bone- osteoporosis in humans. models by generating conditional alleles forming cells,” continues Warman. Sarah Price that could be activated or inactivated “Instead, therapies that can mimic in different cell types, in animals of what the HBM mutations in LRP5 do different ages or in cells at different in osteocytes can be just as effective at Original article Cui, Y. et al. Lrp5 functions in bone to regulate bone mass. Nat. Med. doi:10.1038/nm.2388 stages of differentiation. This approach increasing bone mass and bone strength.” NATURE REVIEWS | RHEUMATOLOGY VOLUME 7 | JULY 2011 © 2011 Macmillan Publishers Limited. All rights reserved.