The accelerated hypertrophy in Pth1r mutant mice might be caused not only by the accelerated differentiation of proliferative cells into hypertrophic cells, but also by the accelerated differentiation of resting cells into proliferative cells. Given that Ihh acts to promote the differentiation of resting to proliferative cells and Ihh-KO mice display markedly reduced proliferation, with hypertrophy at inappropriate positions, it is reasonable to propose that the enhanced Ihh expression might stimulate the proliferation of resting chondrocytes accompanied by an increase in Col2a1 expression, leading to narrowing of the RZ and PZ, in close coordination with accelerated hypertrophy in the TWS119 Slc39a14-KO growth plate. However, the morphological abnormality of the Slc39a14-KO growth plate was less severe than that of the Pth1r mutant. It is possible that other Zn RG7204 transporters and/or Zn-permeable channels have similar functions as the SLC39A14 protein, although their mRNA expression levels were not altered by the loss of SLC39A14. This issue remains to be clarified. Nonetheless, the intracellular Zn level was significantly reduced in the PZ but not the HZ in the Slc39a14-KO mice, reflecting the expression pattern of Slc39a14 in the growth plate. Our results collectively indicate that SLC39A14 plays an indispensable role in proper chondrocyte differentiation in the growth plate, by positively regulating PTH1R-mediated signaling. Besides PTHrP-PTH1R signaling, the role of the GH-IGF-I axis in longitudinal bone growth is well established. It has been suggested that GH acts locally at the growth plate to induce IGF-I production, which then stimulates the proliferation of chondrocytes in a paracrine/autocrine manner, or induces resting chondrocytes to enter a proliferative state, independent of endocrine or paracrine IGF-I. The Slc3914-KO mice showed significant decreases in their plasma concentrations of GH and IGF-I, correlating with a low Zn level in the pituitary gland. In sharp contrast to mice lacking the Ghr gene, which have a normal birth weight and size, the Slc39a14-KO mice had a reduced birth weight and size. In addition, the growth plates of Igf-I-deficient mice display reduced hypertrophy, whereas hypertrophy was augmented in the Slc39a14-KO mice. Therefore, it is unlikely that the reduced GH and IGF-I levels impair chondrocyte differentiation in the Slc39a14-KO mice; rather, their role is probably related to the postnatal systemic growth retardation of these mice. However, we do not exclude the possibility that the reduced IGF-I level has an effect on growth during gestation, because Igf-1-deficient mice show intrauterine growth retardation with low birth weights ; therefore this issue requires further clarification. Nonetheless, it seems likely that in systemic growth, SLC39A14 plays an important role in controlling GH production by regulating the basal cAMP level in GHRHR-mediated signaling. This highlights SLC39A149s importance as a positive GPCR regulator, not only in endochondral ossification, but also in GH production, thus concomitantly regulating systemic growth through these processes.