Abstract
Although Lrp5 is known to be an important contributor to the mechanisms regulating bone mass, its precise role remains unclear. The aim of this study was to establish whether mutations in Lrp5 are associated with differences in the growth and/or apoptosis of osteoblast-like cells and their proliferative response to mechanical strain in vitro. Primary osteoblast-like cells were derived from cortical bone of adult mice lacking functional Lrp5 (Lrp5−/−), those heterozygous for the human G171V High Bone Mass (HBM) mutation (LRP5 G171V) and their WT littermates (WTLrp5, WTHBM). Osteoblast proliferation over time was significantly higher in cultures of cells from LRP5 G171V mice compared to their WTHBM littermates, and lower in Lrp5−/− cells. Cells from female LRP5 G171V mice grew more rapidly than those from males, whereas cells from female Lrp5−/− mice grew more slowly than those from males. Apoptosis induced by serum withdrawal was significantly higher in cultures from Lrp5−/− mice than in those from WTHBM or LRP5 G171V mice. Exposure to a single short period of dynamic mechanical strain was associated with a significant increase in cell number but this response was unaffected by genotype which also did not change the ‘threshold’ at which cells responded to strain. In conclusion, the data presented here suggest that Lrp5 loss and gain of function mutations result in cell-autonomous alterations in osteoblast proliferation and apoptosis but do not alter the proliferative response of osteoblasts to mechanical strain in vitro.
Highlights
Normal bone homeostasis is achieved by balancing the number and activity of bone forming osteoblasts and bone resorbing osteoclasts
Osteoblast proliferation over time in vitro Primary osteoblast-like cells extracted from the long bones of female and male LRP5G171V and Lrp52/2 mice and their WT
Plays a role in osteoblast proliferation The key finding from this study was that absence of Lrp5 function in osteoblastic cells derived from the cortical bone of adult mice was associated with decreased proliferation as evidenced by an increase in cell population doubling time compared with WTLrp5 cells in vitro
Summary
Normal bone homeostasis is achieved by balancing the number and activity of bone forming osteoblasts and bone resorbing osteoclasts. There is compelling evidence that the co-ordinated activities of many different signalling pathways function to control osteoblast number and activity both basally and in response to mechanical strain [1]. One such pathway is the Wnt pathway. Humans with an inactivating mutation in the Lrp Wnt co-receptor gene have reduced bone mass [6,10,11], whilst individuals with an activating mutation (the G171V mutation) have correspondingly higher than normal bone mass [12,13,14]. Experimental models such as Lrp knockout mice [4] or mice expressing human LRP5 transgene containing the G171V activating mutation (LRP5G171V) [7] generally recapitulate the situation in humans and have low and high bone mass respectively
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