CCN1/Cyr61 Is Required in Osteoblasts for Responsiveness to the Anabolic Activity of PTH

Abstract

CCN1/Cyr61 is a dynamically expressed matricellular protein that serves regulatory functions in multiple tissues. Previous studies from our laboratory demonstrated that CCN1 regulates bone maintenance. Using an osteoblast and osteocyte conditional knockout mouse model (Ccn1 OCN), we found a significant decrease in trabecular and cortical bone mass in vivo, in part through suppression of Wnt signaling since the expression of the Wnt antagonist sclerostin (SOST) is increased in osteoblasts lacking CCN1. It has been established that parathyroid hormone (PTH) signaling also suppresses SOST expression in bone. We therefore investigated the interaction between CCN1 and PTH-mediated responses in this study. We find that loss of Ccn1 in osteoblasts leads to impaired responsiveness to anabolic intermittent PTH treatment in Ccn1 OCN mice in vivo and in osteoblasts from these mice in vitro. Analysis of Ccn1 OCN mice demonstrated a significant decrease in parathyroid hormone receptor-1 (PTH1R) expression in osteoblasts in vivo and in vitro. We investigated the regulatory role of a non-canonical integrin-binding domain of CCN1 because several studies indicate that specific integrins are critical to mechanotransduction, a PTH-dependent response, in bone. These data suggest that CCN1 regulates the expression of PTH1R through interaction with the αvβ3 and/or αvβ5 integrin complexes. Osteoblasts that express a mutant form of CCN1 that cannot interact with αvβ3/β5 integrin demonstrate a significant decrease in mRNA and protein expression of both PTH1R and αv integrin. Overall, these data suggest that the αvβ3/β5-binding domain of CCN1 is required to endow PTH signaling with anabolic activity in bone cells.

Cyr61 delivery promotes angiogenesis during bone fracture repair

“…( 31, 52 ). Similarly, endogenous Cyr61 has been reported to mediate bone formation during development ( 32, 33 ). These studies show roles for Cyr61 in promoting chondrocyte proliferation and regulating key transcription factors involved in chondrogenesis and osteogenesis, such as Sox9 ( 31 ) and Runx2 ( 53 ).…”

“…Cyr61 is a matricellular growth factor that functions as an integrin ligand ( 23-26 ) and integrates into the matrix via its N-terminal heparin binding domain ( 27, 28 ). Cyr61, a product of a growth factor-inducible immediate early gene, is associated with the cell surface and the extracellular matrix ( 27, 29, 30 ), and has been reported to regulate both chondrogenesis and osteogenesis during skeletal development ( 31-33 ). Cyr61 has also been implicated in fracture repair.…”

The role of integrin family in bone metabolism and tumor bone metastasis

“…Integrin α v β 1 mediated the adhesion of OBs to CCN2 and promoted OBs maturation, bone nodule formation, and matrix mineralization [ 29 ]. CCN1 regulated parathyroid hormone receptor-1 (PTH1R) expression by interacting with α V β 3 and/or α V β 5 integrin complex, maintaining the homeostatic regulation of the PTH pathway during osteogenic differentiation [ 30 ].…”

“… Integrins Cell types Potential pathways or binding protein Regulating effects Ref. α v β 3 BMSCs BSP/MMP-2/α v β 3 Promote cell migration [ 18 ] β 1 NCAM/β 1 /cofilin Regulate migration and promote proliferation [ 14 ] α 5 β 1 WISP-1/α 5 β 1 /BMP-2 Enhance cell adhesion, survival and migration [ 20 ] α 2 β 1 Col II/α 2 β 1 /FAK-JNK Increase bone formation and defect healing [ 23 ] α 5 ADSCs circRNA-VGLl3/microRNA-326-5p/α 5 Promote osteogenic differentiation [ 25 ] hPDLSCs microRNA-152-3p/α 5 Promote survival and osteogenic differentiation [ 26 ] α 5 β 1 , α V β 5 osteoblast CCN3/α 5 β 1 , α V β 5 /BMP-4 Promote cell maturation, adhesion and matrix mineralization [ 28 ] α v β 1 α v β 1 /CCN2/FAK/ERK Enhance the adhesion and differentiation of osteoblasts [ 29 ] α V β 3 , α V β 5 CCN1/α V β 3 , α V β 5 / PTH1R Promotes bone anabolism through activation of PTH signaling [ 30 ] α 2 β 1 Col I/α 2 β 1 , α 2 β 1 /ERK Regulate cell differentiation …”

Adipose‑PAS interactions in the context of its localised bio‑engineering potential (Review)

“…The change in uPAR colocalization to integrins from α3β1 to αvβ5 blocks the uPA signalling and activation of ERK or AKT ( 151 ), which functionally represents a shift from a laminin rich environment to a vitronectin rich environment. Interestingly, Wnt signalling can be inhibited by α3β1 complexes ( 152 ), while activation of αvβ5 complexes stimulates Wnt signalling ( 153 ). uPAR complex internalisation by the cell can result in Wnt mediated β-catenin gene transcription due to nuclear colocalization, suggesting that uPAR in complex with β-catenin can be a potent activator of stemness ( 154 ).…”