Bone marrow osteoprogenitors are depleted whereas osteoblasts are expanded independent of the osteogenic vasculature in response to zoledronic acid

Abstract

Zoledronic acid (ZOL) is an antiresorptive drug used to prevent bone loss in a variety of conditions, acting mainly through suppression of osteoclast activity. There is growing evidence that ZOL can also affect cells of the mesenchymal lineage in bone. We present novel data revealing significant changes in the abundance of perivascular mesenchymal stromal cells (MSCs)/osteoprogenitors and osteoblasts following the injection of ZOL, in vivo. In young mice with high bone turnover and an abundance of perivascular osteoprogenitors, ZOL significantly (P < 0.0001) increased new bone formation. This was accompanied by a decline in osterix‐positive osteoprogenitors and a corresponding increase in osteoblasts. However, these effects were not observed in mature mice with low bone turnover. Interestingly, the ZOL‐induced changes in cells of the mesenchymal lineage occurred independently of effects on the osteogenic vasculature. Thus, we demonstrate that a single, clinically relevant dose of ZOL can induce new bone formation in microenvironments enriched for perivascular MSC/osteoprogenitors and high osteogenic potential. This arises from the differentiation of perivascular osterix‐positive MSC/osteoprogenitors into osteoblasts at sites that are innately osteogenic. Collectively, our data demonstrate that ZOL affects multiple cell types in bone and has differential effects depending on the level of bone turnover.—Hughes, R., Chen, X., Hunter, K. D., Hobbs, J. K., Holen, I., Brown, N. J. Bone marrow osteoprogenitors are depleted whereas osteoblasts are expanded independent of the osteogenic vasculature in response to zoledronic acid. FASEB J. 33, 12768–12779 (2019). http://www.fasebj.org

Osteoblast-Derived Paracrine and Juxtacrine Signals Protect Disseminated Breast Cancer Cells from Stress

“…We quantified the numbers of osteoprogenitors in the metaphyses of hind limbs from the indolence and outgrowth models. Consistent with previously published data [ 26 ], osteoprogenitor numbers were significantly reduced in the indolence model ( Figure 3 a). Interestingly, the reduced abundance of osteoprogenitors was associated with a reduced ability of the bone microenvironment to support high numbers of DTCs, a 65% decrease compared with the outgrowth model ( Figure 3 b).…”

“…We next investigated how the repositioning of DTCs between the perivascular and endosteal niches in bone might influence their survival and ability to form overt metastatic lesions. We and others have previously reported a decline in the abundance of type-H CD31pos blood vessels in mature mice [ 10 , 26 ]. Thus, if CD31 pos endothelial cells (ECs) provide proliferative cues to DTCs, a reduction in this EC population could explain the absence of metastatic outgrowth in our model of indolence.…”

Oestrogen and zoledronic acid driven changes to the bone and immune environments: Potential mechanisms underlying the differential anti-tumour effects of zoledronic acid in pre- and post-menopausal conditions

“…Although the mechanisms of how ZOL induced these changes were not investigated, it is likely that the mevalonate pathway was the main target of this drug on the vascular endothelial cells. These findings, however, were not recapitulated in in vivo models where blood vessels are only exposed to ZOL for short periods of time as would be the case in breast cancer patients [46] . When looking at the vasculature and surrounding perivascular cell populations in BALB/c nude mice mature mice (mimicking a pre-menopausal situation) no significant differences in the number of vessels of ZOL treated and untreated animals were observed.…”

“…However, these results indicate that mobilization may not be dependent on osteoclast activity but rather an alternative mechanism to be determined. In contrast, it is the mesenchymal niche where a decrease in the number of osteoprogenitors (Osteoblast-specific transcription factor Osterix (Osx) positive) and an increment in earlier, less committed, osteoprogenitors is observed following administration of ZOL [46] . There is substantial data showing that ZOL reduces osteoblast activity, overall numbers of osteoblasts in bone and genes associated with osteoblast formation [35] , [52] .…”

“…In mouse models, the numbers of osteoblasts significantly increased after a single dose of ZOL but only in regions of intense bone remodelling, commonly the metaphysis in long bones (tibia and femur). Whereas in regions of low rates of bone remodelling, such as cortical bone or low trabecular (for tibia), the number of osteoblasts is significantly decreased [46] , [53] . All of this evidence point to ZOL having dramatic effects on the bone microenvironment, inhibiting bone resorption and limiting expansion of the bone metastatic niches, these are processes thought to be responsible for reducing the ability of tumour cells to colonise and grow in bone.…”