Human bone mass is the result of a fine balancing act between bone deposition — carried out by bone-forming cells called osteoblasts — and degradation by the osteoclasts. In later life, as bone catabolism supersedes anabolism, the result is often a loss of bone mass (osteoporosis). To prevent this condition, we need to know more about the processes that underlie bone formation, and a report in Cell by Matthew Warman and co-workers now takes us a step closer, revealing an intriguing link to the Wingless (Wnt) signalling pathway.

Warman, along with Yaoqin Gong and an international group of clinicians and scientists, started by searching for the gene behind osteoporosis-pseudoglioma syndrome (OPPG) — an autosomal-recessive disorder in which patients have very low bone mass. They studied 28 affected families, and identified six different homozygous frameshift or nonsense mutations in the low-density lipoprotein receptor-related protein-5 ( LRP5 ) gene.

Next the authors looked at expression of mouse Lrp5 messenger RNA during embryogenesis by in situ hybridization on developing skeletal elements. They detected expression in osteoblasts; interestingly, in pluripotent cell lines induced into the osteoblastic lineage by exogenous growth factors, the authors also found increased expression of LRP5. And this could, they speculate, indicate a role for LRP5 in terminal osteoblastic differentiation.

To delve deeper into the function of LRP5, Warman and co-workers used what is already known about its relatives. The mouse, Xenopus laevis and Drosophila melanogaster paralogues of LRP5 are involved in the Wnt signalling cascade, so the authors examined the effects of expressing various Wnt proteins in vitro.

To do this they used alkaline phosphatase (ALP) as a marker of osteoblast differentiation in the two pluripotent mesenchymal cell lines. Whereas WNT3a — which participates in the canonical Wnt signalling pathway — could induce ALP activity in both lines, WNT5a and WNT4 (which use other signalling pathways) could not. WNT3a-induced ALP activity was also reduced when dominant-negative forms of LRP5 that lack the cytoplasmic tail were expressed in these cell lines. Moreover, induction of ALP by WNT3a could be blocked by coexpression with a dominant-negative form of Dishevelled, which acts downstream of WNT3a in the canonical pathway.

Finally, Warman and colleagues studied the effect of culturing bone explants in conditioned media from cells expressing the secreted form of LRP5, which could act as a decoy receptor. In three independent experiments they showed that these explants had lower bone mass than did explants cultured in media from cells expressing the wild-type, non-secreted form of LRP5. The authors additionally found that carriers of OPPG mutations also have reduced bone mass compared with non-carrier controls, suggesting that the activity of LRP5 is dosage sensitive.

These impressive results not only implicate LRP5 in the acquisition of bone mass, but they provide a clue as to how it does this. Given that LRP5 is expressed in several different tissues, one surprise is that the phenotypic effects of the mutation seem to appear only in the skeleton and the eye. This could mean that the functions of LRP5 are redundant or that it binds to other ligands too — questions that will need to be answered if pharmacological modulation of LRP5 is to be used in the fight against osteoporosis.