Oral Presentation 1st Asia Pacific Herbert Fleisch Workshop 2025

Skeletal stem/progenitor cells (SSPCs) contribute to the anabolic actions of intermittent PTH through PDGF receptor signalling (#27)

Johanna Besold 1 2 3 , Chloë Goossens 1 , Ruben Cardoen 1 , Elena Nefyodova 1 , Natalie Sims 2 3 , Christa Maes 1
  1. Laboratory of Skeletal Cell Biology and Physiology (SCEBP), Skeletal Biology and Engineering Research Center (SBE), Department of Development and Regeneration, KU Leuven, Leuven, Belgium
  2. St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia
  3. Department of Medicine at St. Vincent’s Hospital, The University of Melbourne, Melbourne, Australia

Skeletal stem/progenitor cells (SSPCs) in the bone marrow are a crucial source of osteoblasts in postnatal bones. Intermittent parathyroid hormone (iPTH), a bone-building osteoporosis treatment, increases osteoblast number and bone formation, but has limited efficacy. A better understanding of the progenitors and signals contributing to iPTH’s anabolic effect could lead to improved therapies. Since SSPCs marked by platelet‐derived growth factor receptor (PDGFR) expression rebuild bone after fracture, we tested whether iPTH also activates this population to become osteoblasts, and whether PDGFR signalling contributes to this process.

 

iPTH-administration (80µg/kg, 10 daily injections in mice) significantly elevated PDGF ligand and receptor transcripts in bone (qRT-PCR), supporting PDGF-PDGFR pathway involvement. Flow cytometry showed that the numbers of PDGFRα/β-expressing SSPCs significantly declined after only three days of iPTH, and revealed a shift in the numbers of primitive skeletal stem cells (-17%) toward more committed progenitors (+30%) after 10 days (P<0.001). To map the response of PDGFRβ-expressing SSPCs to iPTH, we genetically labelled and lineage-traced PDGFRβ-CreERt;Ai9+ cells, in mice with Col1-GFP-labelling of osteoblasts. Histological analysis revealed that the population of PDGFRβ/Ai9+ SSPCs vigorously proliferated and expanded after 10 days iPTH. After 4 weeks of treatment, a subset of PDGFRβ-descendants had become Col1-GFP+ osteoblasts. Thus, iPTH stimulates proliferation of PDGFR+ SSPCs and their subsequent osteoblast commitment and differentiation.

To test whether PDGFR signalling is required for iPTH-induced bone formation, we generated mice lacking PDGFRα/β in SSPCs and their descendants using Prrx1-Cre. While four weeks of iPTH (80µg/kg) significantly increased osteoblast numbers (+3.5-fold), trabecular thickness (+38%) and mineralising surfaces (+60%) in control mice, the conditional PDGFRα/β-inactivation blocked all these effects, indicating that PDGFR signalling mediates iPTH’s bone-building actions.

 

In conclusion, our work reveals that PDGFRβ+ SSPCs respond to iPTH and identifies the PDGF-PDGFR pathway as molecular target of iPTH, suggesting that its modulation could have therapeutic potential.