Reduced ß-catenin expression affects patterning of bone primordia, but not bone maturation.

Wnt/ß-catenin signaling is involved in patterning of bone primordia, but also plays an important role in the differentiation of chondrocytes and osteoblasts. During these processes the level of ß-catenin must be tightly regulated. Excess ß-catenin leads to conditions with increased bone mass, whereas loss of ß-catenin is associated with osteoporosis or, in extreme cases, the absence of limbs. In this study, we examined skeletogenesis in mice, which retain only 25% of ß-catenin. These embryos showed severe morphological abnormalities of which the lack of hindlimbs and misshaped front paws were the most striking. Surprisingly however, calcification of bone primordia occurred normally. Moreover, the Wnt-dependent regulatory network of transcription factors driving the differentiation of cartilage and bone, as well as the expression of extracellular matrix components, were preserved. These findings show that 25% ß-catenin is insufficient for the correct patterning of bone primordia, but sufficient for their mineralization. Our approach helps to identify bone morphogenetic processes that can proceed normally even at low ß-catenin levels, in contrast to those that require high ß-catenin dosages. This information could be exploited to improve the treatment of bone diseases by fine-tuning the individual ß-catenin dosage requirements.