ESPE Yearbook of Paediatric Endocrinology

Bone. 2021 Jan;142:115709 Abstract: https://pubmed.ncbi.nlm.nih.gov/33148508/

In brief: In the developing bone, PTHrP signaling inhibits hypertrophic differentiation, the key step in the coupling of chondrogenesis and osteogenesis during endochondral bone formation. The current paper reviews findings of previous knockout-studies on PTHrP-induced signaling including HDAC4/5, salt-inducible kinases and transcription factors MEf2 and Runx2 and, for the first time, outlines the molecular mechanisms by which PTHrP controls chondrocyte hypertrophy.

Comment: The feedback loop between PTHrP and Indian hedgehog IHH represents a crucial regulating mechanism of growth plate chondrocyte differentiation in vivo. The essential role of PTHrP is exerted by inhibition of chondrocyte hypertrophy while IHH, synthesized by postproliferational chondrocytes, is essential for the synthesis of PTHrP in early differentiation stages. Thus, the balance between the two factors controls the pace of growth plate chondrocyte differentiation.

While the physiologic role of PTHrP has been investigated in several knockout models, the precise mechanism of inhibition of chondrocyte hypertrophy remained incompletely understood. As reported in the ESPE Yearbook 2020, Nishimori et al. identified both salt-inducible kinases as well as their substrates HDAC4 and HDAC5 as key components of PTHrP signaling in growth plate chondrocytes. Here, the authors merge findings and conclusions of their group as well as others on PTHrP induced regulatory cascades. The resulting hypothesis postulates a key role of PTHrP-induced HDAC4 nuclear translocation by direct inhibition of Sik3 kinase activity. Nuclear HDAC4 then blocks specific transcription factors MEf2 and Runx2, resulting in a halt of differentiation specific genes and inhibition of chondrocyte hypertrophy.

Since PTHrP is a master regulator in growth plate physiology, the deepened understanding of its major function reviewed here represents a milestone in the understanding of endochondral bone formation.