Adverse Effects of Osteocytic Constitutive Activation of ß-Catenin on Bone Strength and Bone Growth

Abstract

The activation of the canonical Wnt/b-catenin signaling pathway in both mesenchymal stem cells and osteoblasts has been demonstrated to increase bone mass, showing promise for the treatment of low bone volume conditions such as osteoporosis. However, the possible side effects of manipulating this pathway have not been fully addressed. Previously, we reported that the constitutive activation of ß-catenin in osteoblasts impaired vertebral linear growth. In the present study, b-catenin was constitutively activated in osteocytes by crossing Catnbþ/lox(exon 3) mice with dentin matrix protein 1(DMP1)-Cre transgenic mice, and the effects of this activation on bone mass, bone growth and bone strength were then observed. DMP1-Cre was found to be predominantly expressed in osteocytes, with weak expression in a small portion of osteoblasts and growth plate chondrocytes. After the activation, the cancellous bone mass was dramatically increased, almost filling the entire bone marrow cavity in long bones. However, bone strength decreased significantly. Thinner and more porous cortical bone along with impaired mineralization were responsible for the decrease in bone strength. Furthermore, the mice showed shorter stature with impaired linear growth of the long bones. Moreover, the concentration of serum phosphate decreased significantly after the activation of ß-catenin, and a high inorganic phosphate (Pi) diet could partially rescue the phenotype of decreased mineralization level and impaired linear growth. Taken together, the constitutive activation of b-catenin in osteocytes may increase cancellous bone mass; however, the activation also had adverse effects on bone strength and bone growth. These adverse effects should be addressed before the adoption of any therapeutic clinical application involving adjustment of the Wnt/b-catenin signaling pathway.

Mouse Cre Models for the Study of Bone Diseases

“…Deletion of Fgfr1 in osteocytes using Dmp1-Cre showed a dramatic reduction in FGF23 expression and serum FGF23 concentrations, suggesting an important role for osteocyte FGFR1 signaling in phosphate regulation [2]. An example of the 10kb Dmp1-Cre being used for gene activation is from the study of Chen et al [20], in which β-catenin was constitutively activated in osteocytes by crossing Catnb+/lox(exon 3) mice with the 10kb Dmp1-Cre mice. These mice showed increased cancellous bone mass, but surprisingly showed reduced bone strength due to cortical thinning and increased cortical porosity.…”

Osteoblastic heparan sulfate glycosaminoglycans control bone remodeling by regulating Wnt signaling and the crosstalk between bone surface and marrow cells

“…41, 42 Overactivation of β-catenin in osteocytes and mature osteoblasts results in decreased bone quality and growth. 43 Hence, inhibition of Wnt signaling can affect precursor cells within bone marrow and at the same time promote osteoblast activity.…”

Endothelin Signaling in Bone

“…WNT signaling has an unequivocal trophic impact on cells already committed to the osteoblast lineage; indeed, canonical WNT signaling has been shown by some investigators to inhibit commitment of mesenchymal stem cells to the osteoblast lineage 44,45 . In addition, mice constitutively expressing β-catenin in late stage osteoblasts and osteocytes have both increased bone volume and osteomalacia 46 . These findings demonstrate that normal bone mineralization requires down-regulation of canonical WNT signaling at late stages of osteoblast maturation, even while elaboration of bone matrix by less mature cells is promoted.…”