The distinct roles of PTHrP and PTH1R in long bone growth and digit formation

PTH-related peptide (PTHrP) and its receptor, the PTH/PTHrP receptor type 1 (PTH1R), are essential for chondrocyte differentiation and epiphyseal cartilage homeostasis. To evaluate the functional differences between PTHrP and PTH1R derived from mesenchymal progenitor cells (MPCs) in skeletal development, we generated MPC-specific Pthrp conditional KO mice (PTHrP cKO; Prrx1-Cre; Pthrp ^flox/flox) or Pth1r cKO mice (PTH1R cKO; Prrx1-Cre; Pth1r ^flox/flox) using the Prrx1-Cre driver and analyzed their skeletal phenotypes. Both PTHrP cKO mice and PTH1R cKO mice exhibited severe shortening of long bones and impaired growth plate formation immediately after birth. However, in the digits, only PTHrP cKO mice showed distinctive digit deviations in the toes, which were similar to those seen in human diastrophic dysplasia (DTD). These results suggest that MPC-derived PTHrP and PTH1R play distinct roles. Both are essential for longitudinal bone growth, but PTHrP plays an important role in regulating toe position and morphology. This phenotypic difference suggests a novel PTH1R-independent function of PTHrP in skeletal development. Thus, our study provides genetic evidence for this mechanism, offering insights into the pathogenesis of congenital digit deformities such as those seen in DTD.