Fig. 8. PTHrP and BMP signaling interact to initiate mammary bud outgrowth and nipple formation. PTHrP is secreted from mammary epithelial cells and increases BMPR1A expression in the mammary mesenchyme. This increases the sensitivity of these cells to BMPs and allows them to respond to BMP4 in a paracrine and/or autocrine fashion. BMP4 signaling in the mesenchyme, in turn, triggers epithelial outgrowth and augments MSX2 expression, which causes the mammary mesenchyme to inhibit hair follicle formation within the nipple sheath.