Full Length or Fragments in Hormone Studies?

Abstract

We fully agree with Dr Martin that our study has specifically addressed the role of amino terminal fragments of PTH-related protein (PTHrP) and PTH in osteoblast differentiation. The effects of both fragments are mediated by the PTH/PTHrP type 1 receptor (PTHR1), and in concordance with extensive data, we did not observe a difference in effect of both hormone fragments. With respect to the role of PTHrP in osteoblast differentiation, many questions are still unresolved.First, PTHrP is a prepro-hormone subject to proteolytic processing.(1) Various N-terminal, midregional, and Cterminal fragments can be formed, each with its own proposed function. It is still unknown to what extent proteolytic processing of PTHrP occurs in osteoblasts and what is the dominant PTHrP fragment presented to the osteoblasts in vivo. This may well be full-length PTHrP as suggested by Dr Martin, but in our opinion, there is as yet no conclusive evidence for this.Second, whether and how C-terminal domains of PTHrP influence the biological activity of its N-terminal PTH-like domain is still largely unknown. This would require a detailed side-by side comparison of various naturally occurring N-terminal fragments of PTHrP [e.g., PTHrP(1-36), PTHrP(1-84), or PTHrP(1-139)]. These comparisons are currently lacking, most likely because of limited availability of the longer fragments.Third, whether PTHrP is having effects on osteoblast differentiation not mediated by the PTHR1 is a matter of debate. Some evidence for such a role for PTHrP comes from detailed comparison of the bone phenotype of PTHR1, PTHrP, and double null mice performed by Lanske et al.(2) The delay in vascular invasion in primary ossification centers observed in the PTHR1 null mice is not reversed in the double null mice, indicating that this effect of PTHrP is not mediated by the PTHR1. Whether osteoblasts are involved in this effect is, however, unclear. Limited and conflicting data suggest a role for C-terminal PTHrP fragments [e.g., PTHrP(107-111)] on osteoblast proliferation being either stimulatory or inhibitory, (3,4) but this issue needs more study.Nevertheless, we agree with Dr Martin that there are many unresolved issues regarding the auto-and paracrine role of PTHrP in osteoblast differentiation. Our study has addressed only a part of this role. There is a clear need for additional studies to clarify these unresolved functions of PTHrP in osteoblast biology.

Interaction between immuno-stem dual lineages in jaw bone formation and injury repair

“…Recently, Hu et al reported that Piezo1 activation promotes osteogenic differentiation of Gli1 + MSCs by activating the Wnt/β-catenin signaling pathway (HU et al, 2023). Moreover, TGF-β/BMP signal and Hh signal have been confirmed to have a synergistic effect on the osteogenic differentiation of MSCs, activation of both increases osteogenic potential of MSCs ( VAN DER HORST et al, 2003;REICHERT et al, 2013). The relationship between the Hh and Wnt signaling pathways is particularly complex.…”