Intermittent PTH Administration Increases Bone-Specific Blood Vessels and Surrounding Stromal Cells in Murine Long Bones

Abstract

To verify whether PTH acts on bone-specific blood vessels and on cells surrounding these blood vessels, 6-weeks-old male mice were subjected to vehicle (control group) or hPTH (20 µg/kg/day, PTH group) injections for 2 weeks.Femoral metaphyses were used for histochemical and immunohistochemical studies. In control metaphyses, endomucin-positive blood vessels were abundant, but SMA-reactive blood vessels were scarce. In the PTHadministered mice, the lumen of endomucin-positive blood vessels was markedly-enlarged.Moreover, many SMA-positive cells were evident near the blood vessels, and seemed to derive from those vessels. These SMA-positive cells neighboring the blood vessels showed features of mesenchymal stromal cells, such as immunopositivity for c-kit and tissue nonspecific alkaline phosphatase (TNALP). Thus, PTH administration increased the population of perivascular/stromal cells positive for αSMA and c-kit, which were likely committed to the osteoblastic lineage. To understand the cellular events that led to increased numbers and size of bone-specific blood vessels, we performed immunohistochemical studies for PTH/PTHrP receptor and VEGF. After PTH administration, PTH/PTHrP receptor, VEGF and its receptor flk-1 were consistently identified in both osteoblasts and blood vessels (endothelial cells and surrounding perivascular cells). Our findings suggest that exogenous PTH increases the number and size of bone-specific blood vessels while fostering perivascular/stromal cells positive for αSMA/TNALP/c-kit.

PTH-Induced Bone Regeneration and Vascular Modulation Are Both Dependent on Endothelial Signaling

“…PTH has been well-established as an inducer of osteogenesis in the osteoporotic patient and has been used in the treatment of various bone fractures in both osteoporotic and non-osteoporotic patients. This study, as well as the work of others, demonstrates that PTH also plays a role in directing the vascular tree towards intact bone [ 40 ] and towards the site of a fracture [ 21 , 25 ]. The osteogenic process required to achieve bone formation has been shown to rely on active vascularization, which is modulated by PTH both directly [ 41 ] and indirectly [ 31 ].…”

Gli1+-PDL Cells Contribute to Alveolar Bone Homeostasis and Regeneration

“…Since endomucin, a marker of vascular endothelial cells (Kusumbe et al 2014; Zhao, Hasegawa, et al 2021), was localized around the blood vessels of the PDL, most Gli1/Tomato + cells were thought to be distributed near blood vessels (Fig. 1F).…”

Histochemical characteristics on minimodeling-based bone formation induced by anabolic drugs for osteoporotic treatment

“…Using PTH-administered animal models, we have reported that PTH stimulates the proliferation of preosteoblastic cells (Luiz de Freitas et al, 2009) (Fig. 4), as well as differentiation of perivascular cells surrounding endomucin-positive blood vessels into osteoblastic progenitors (Zhao et al, 2021). Luiz de Freitas et al (2009) have previously reported that intermittent PTH administration did not facilitate osteoblastic bone formation in the absence of osteoclasts, indicating that the PTH-driven anabolic effect depends on cell coupling from osteoclasts.…”