TY - JOUR
T1 - Role of Prx1-expressing skeletal cells and Prx1-expression in fracture repair
AU - Esposito, Alessandra
AU - Wang, Lai
AU - Li, Tieshi
AU - Miranda, Mariana
AU - Spagnoli, Anna
N1 - Funding Information:
This work was supported by a grant from National Institutes of Health- National Institute of Arthritis and Musculoskeletal and Skin Diseases ( 1R01AR074049-01 ) to A.S.
Funding Information:
We acknowledge the support of Dr. Ping Ye at University of North Carolina at Chapel Hill in assisting in the cell-tracing studies. We acknowledge the support of M.E. Cruz in assisting in the preparation of the figures and the support of M.R. Sandbulte in proofreading the manuscript. We acknowledge the support of J.D. Temple in assisting in the ?CT studies. We acknowledge the Flow Cytometry Core at University of Illinois at Chicago and the Rush Internal Medicine Drug Discovery and Imaging Core for their technical assistance. We are grateful to S. Murakami (Case Western Reserve University) for providing the Prx1-CreER transgenic mice and to Dr. James Martin (Texas A&M Health Science Center, Houston, TX) for providing the BMP2flox/flox transgenic mice. This work was supported by a grant from National Institutes of Health-National Institute of Arthritis and Musculoskeletal and Skin Diseases (1R01AR074049-01) to A.S.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/10
Y1 - 2020/10
N2 - The healing capacity of bones after fracture implies the existence of adult regenerative cells. However, information on identification and functional role of fracture-induced progenitors is still lacking. Paired-related homeobox 1 (Prx1) is expressed during skeletogenesis. We hypothesize that fracture recapitulates Prx1's expression, and Prx1 expressing cells are critical to induce repair. To address our hypothesis, we used a combination of in vivo and in vitro approaches, short and long-term cell tracking analyses of progenies and actively expressing cells, cell ablation studies, and rodent animal models for normal and defective fracture healing. We found that fracture elicits a periosteal and endosteal response of perivascular Prx1+ cells that participate in fracture healing and showed that Prx1-expressing cells have a functional role in the repair process. While Prx1-derived cells contribute to the callus, Prx1's expression decreases concurrently with differentiation into cartilaginous and bone cells, similarly to when Prx1+ cells are cultured in differentiating conditions. We determined that bone morphogenic protein 2 (BMP2), through C-X-C motif-ligand-12 (CXCL12) signaling, modulates the downregulation of Prx1. We demonstrated that fracture elicits an early increase in BMP2 expression, followed by a decrease in CXCL12 that in turn down-regulates Prx1, allowing cells to commit to osteochondrogenesis. In vivo and in vitro treatment with CXCR4 antagonist AMD3100 restored Prx1 expression by modulating the BMP2-CXCL12 axis. Our studies represent a shift in the current research that has primarily focused on the identification of markers for postnatal skeletal progenitors, and instead we characterized the function of a specific population (Prx1+ cells) and their expression marker (Prx1) as a crossroad in fracture repair. The identification of fracture-induced perivascular Prx1+ cells and regulation of Prx1's expression by BMP2 and in turn by CXCL12 in the orchestration of fracture repair, highlights a pathway in which to investigate defective mechanisms and therapeutic targets for fracture non-union.
AB - The healing capacity of bones after fracture implies the existence of adult regenerative cells. However, information on identification and functional role of fracture-induced progenitors is still lacking. Paired-related homeobox 1 (Prx1) is expressed during skeletogenesis. We hypothesize that fracture recapitulates Prx1's expression, and Prx1 expressing cells are critical to induce repair. To address our hypothesis, we used a combination of in vivo and in vitro approaches, short and long-term cell tracking analyses of progenies and actively expressing cells, cell ablation studies, and rodent animal models for normal and defective fracture healing. We found that fracture elicits a periosteal and endosteal response of perivascular Prx1+ cells that participate in fracture healing and showed that Prx1-expressing cells have a functional role in the repair process. While Prx1-derived cells contribute to the callus, Prx1's expression decreases concurrently with differentiation into cartilaginous and bone cells, similarly to when Prx1+ cells are cultured in differentiating conditions. We determined that bone morphogenic protein 2 (BMP2), through C-X-C motif-ligand-12 (CXCL12) signaling, modulates the downregulation of Prx1. We demonstrated that fracture elicits an early increase in BMP2 expression, followed by a decrease in CXCL12 that in turn down-regulates Prx1, allowing cells to commit to osteochondrogenesis. In vivo and in vitro treatment with CXCR4 antagonist AMD3100 restored Prx1 expression by modulating the BMP2-CXCL12 axis. Our studies represent a shift in the current research that has primarily focused on the identification of markers for postnatal skeletal progenitors, and instead we characterized the function of a specific population (Prx1+ cells) and their expression marker (Prx1) as a crossroad in fracture repair. The identification of fracture-induced perivascular Prx1+ cells and regulation of Prx1's expression by BMP2 and in turn by CXCL12 in the orchestration of fracture repair, highlights a pathway in which to investigate defective mechanisms and therapeutic targets for fracture non-union.
KW - BMP2
KW - CXCL12
KW - Fracture healing
KW - Progenitor
KW - Prx1
KW - Skeletal cells
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U2 - 10.1016/j.bone.2020.115521
DO - 10.1016/j.bone.2020.115521
M3 - Article
C2 - 32629173
AN - SCOPUS:85088019101
VL - 139
JO - Bone
JF - Bone
SN - 8756-3282
M1 - 115521
ER -