The ability to quantify macroscopic physiological parameters such as tissue contractile force and matrix elasticity cannot be achieved using current in vitro 2D cell culture systems. This study demonstrated that HCMV disrupts the mechanical force established by human fibroblasts within tissues and it is conceivable that the resulting tissue damage may contribute to the diverse pathologies associated with persistent HCMV infection in vivo. Several lines of evidence indicate that signaling triggered by CNP plays an important role in chondrocyte development. Upon CNP binding, its cognate receptor natriuretic peptide receptor 2 functions as a guanylyl cyclase to increase cyclic guanosine monophosphate levels in chondrocytes, female reproductive organs, and endothelial cells. Transgenic mice that overproduce CNP exhibit excessive growth, while defects of the CNP or Npr2 gene, leading to impairment of skeletal development. The increase in cGMP level activates cGMP-dependent protein kinase II and seems to promote the accumulation of extracellular matrix in the growth plate of CNPtransgenic mice. In human, overproduction of C-type natriuretic peptide due to a chromosomal translocation was reported to cause skeletal dysplasia associated with tall stature. In addition, acromesomelic dysplasia, type Maroteaux, ABT-199 characterized by dwarfism and short limbs, is caused by loss-offunction mutations in the Npr2 gene. On the other hand, NPR3, which is thought to act as a clearance receptor, knock-out mice resemble CNP transgenic mice. In this paper, we describe the first family with tall stature and macrodactyly of both great toes caused by a gain-of-function type mutation in the Npr2 gene. The mutant receptor, p.Val883Met, constitutively generates cGMP in vitro. Animal studies using the transgenic mice expressing the mutant NPR2 in chondrocytes demonstrated that skeletal overgrowth was associated with the overproduction of cGMP in cartilage. Our findings provide evidence that cGMP production downstream CNP/NPR2 system regulates the proliferation and differentiation of chondrocytes and determines skeletal growth. Here we have described a three-generation family with tall stature and macrodactyly due to a newly identified gain-offunction mutation of the Npr2 gene, p.Val883Met. Increased levels of cGMP both in blood samples of the patients and whole cell lysates expressing the mutant receptor clearly indicate its hypermorphism. Transgenic mice in which p.Val883Met mutant NPR2 was expressed in chondrocytes exhibited the elevated cGMP concentration and the excessive growth and deformities of vertebrae and long bones, which reproduced the symptoms observed in the patients. Taken together, our data are compatible with the interpretation that p.Val883Met mutant is constitutively active and causes skeletal overgrowth by increasing the level of cGMP in chondrocytes. However, we cannot exclude the possibility that the high expression level of NPR2 also contributed to overgrowth in transgenic mice to some extent. Histological examination confirmed that the skeletal overgrowth was caused by the widening of the growth plates in the transgenic mice expressing the mutant Npr2. As expected, the histological finding was similar to, but severer than, that reported in the mice with overexpression of CNP in chondrocytes. The disorganized arrangement of chondrocytes in the transgenic mice indicates the critical role of the CNP/NPR2 pathway in chondrogenesis.