Ecto-5′-nucleotidase (CD73) regulates bone formation and remodeling during intramembranous bone repair in aging mice

Abstract

Ecto-5′-nucleotidase (CD73) generates adenosine, an osteoblast activator and key regulator of skeletal growth. It is unknown, however, if CD73 regulates osteogenic differentiation during fracture healing in adulthood, and in particular how CD73 activity regulates intramembranous bone repair in the elderly by using a CD73 knock-out (CD73−/−) mouse model. Monocortical tibial defects were created in 46 to 52-week-old wild type (WT) and CD73−/− mice. Injury repair was analyzed at post-operative days 5, 7, 14 and 21 by micro-computed tomography (micro-CT), histomorphometry, proliferating cell nuclear antigen (PCNA) immunostaining, alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) histochemistry. Aged CD73 knock-out mice exhibited delayed bone regeneration and significantly reduced bone matrix deposition during bone healing detected by histomorphometry and micro-CT. Cell proliferation, ALP activity and osteoclast number were reduced in the CD73−/− mice, suggesting a combined defect in bone formation and resorption due the absence of CD73 activity in this model of intramembranous bone repair. Results from this study demonstrate that osteoblast activation through CD73 activity is essential during bone repair in aged mice, and it may present a drugable target for future biomimetic therapeutic approaches that aim at enhancing bone formation in the elderly patients.

Identification of ALP+/CD73+ defining markers for enhanced osteogenic potential in human adipose-derived mesenchymal stromal cells by mass cytometry

“…Although ALP and CD73 have never been associated together with osteogenic potential, singularly they were previously correlated with osteogenic differentiation. CD73 was shown to regulate bone formation and remodeling in intramembranous bone repair [ 48 ]. In our study, we demonstrated that CD73 expression levels inversely correlate with the osteogenic differentiation ability of 17 human AD-MSC primary preparations (Figs.…”

Effect of cell culture density on dental pulp-derived mesenchymal stem cells with reference to osteogenic differentiation

“…CD73, ecto-5′-nucleotidase, is also a typical MSC marker, and induces bone formation via the synthesis of adenosine, an osteoblast activator and key regulator 20,21 . The CD73 inhibitor adenosine 5′-(α,β-methylene) diphosphate induces chondrogenic matrix deposition, but reduces mineral matrix deposition and the expression of osteogenic markers 22 .…”

Signaling of the Purinergic System in the Joint

“…Patients with mutations in the ADA gene and the consequent increase in adenosine availability, present radiological bone defect including scapular and ribs changes, alteration due to imbalance between osteoclasts and osteoblasts functions resulting in low bone formation (Cederbaum et al, 1976;Sauer et al, 2009;Manson et al, 2013). mRNA of CD39 and CD73 is expressed in precursor and mature osteoclasts and mice lacking CD73 have osteopenia associated with a higher number of osteoclasts compared to control mice and present a delay in bone regeneration due to an impairment in osteoblast activity (Takedachi et al, 2012;Bradaschia-Correa et al, 2017). Administration of Dipyridamole (440 mg/day), a drug that blocks adenosine re-uptake increasing its extracellular availability, was tested on RA patients and it has been shown that the drug does not raise blood purine levels and does not change patients symptoms .…”