The Calcineurin-NFAT Pathway and Bone: Intriguing New Findings

Findings from three recent studies on effects of the calcineurin-NFAT pathway in osteoblasts. A. Overexpression of calcineurin increases the expression of the bone differentiation markers alkaline phosphatase, osteocalcin, bone sialoprotein (BSP), and Runx-2 20). B. Expression of NFATc1 increases the gene expression from the collagen 1a1 promoter and also increases the number of bone nodules (i.e., NFATc1 expression promotes bone formation) (16). NFATc1 forms a complex with the transcription factor Osterix. C. When a nuclear NFATc1 mutant (NFATc1^nuc) is expressed in mice, expression of the mutant in bone is observed solely in osteoblasts (17). There was concomitant osteoblast proliferation, increased expression of Wnt4 and Frizzled 9, and decreased secreted frizzled-related protein 2 (SFRP2) and the Wnt antagonist dickkopf2 (DKK2). The expression of chemokine CCL8 was increased and osteoclastogenesis—whereby the fusion of precursor cells (not shown) to form mature multinucleated osteoclasts—was stimulated. Blue cells represent osteoblasts; the red cell represent a mature osteoclast.