Circulating fibronectin affects bone matrix, whereas osteoblast fibronectin modulates osteoblast function

Abstract

The bone matrix is composed mostly of collagen, but the initial and continuous presence of fibronectin was found to be crucial for collagen matrix integrity in vitro. It has been assumed that osteoblasts produce the fibronectin required for bone matrix formation. Using transgenic mice, we conditionally deleted fibronectin in the osteoblasts and in the liver using the cre-loxP system. We also used mice with mutated fibronectin and conditionally deleted b 1 -integrin in osteoblasts to identify the receptor involved in fibronectin effects on osteoblasts. Conditional deletion of fibronectin in the differentiating osteoblasts [using the 2.3 kb collagen-a1(I) promoter] failed to show a decrease in fibronectin amount in the bone matrix despite evidence of successful deletion. Using these mice we established that osteoblast-derived fibronectin solely affects osteoblast function. This effect was not mediated by integrins that bind to the RGD motif. Conditional deletion of fibronectin in the liver showed a marked decrease in fibronectin content in the matrix associated with decreased mineral-to-matrix ratio and changed biomechanical properties but had no effect on osteoblasts or osteoclasts. In conclusion, osteoblast fibronectin affects osteoblasts function. This does not seem to be mediated by the RGD motif on fibronectin. In contrast, liver-derived fibronectin affects bone matrix properties without affecting osteoblast or osteoclast function. A novel role for liver-derived circulating fibronectin thus was defined and delineated from that of locally produced fibronectin. ß

Factor XIII-A transglutaminase acts as a switch between preadipocyte proliferation and differentiation

“…36,48,[66][67][68] Our work is the first to demonstrate that pFN, synthesized by hepatocytes in liver, contributes to adipogenesis. This adds to the list of tissues (liver, brain, testis, heart, lungs, and bone 37,38 ) and cell types that have been shown to accumulate pFN for their function. 32,33 Furthermore, although FN matrix is clearly an important component of WAT and preadipocyte cultures, its actual function has remained elusive.…”

“…35,36 In the physiological setting, FN exists as 2 pools: as cellular FN (cFN) synthesized by tissue-resident cells and as plasma FN (pFN) produced by the liver. 31 pFN has recently been shown to accumulate from the circulation into several tissues (liver, brain, testis, heart, lungs, and bone), 37,38 and to contribute to the majority of the FN extracellular matrix associated with several cell types. 16,[31][32][33] FXIII-A has been shown to increase FN matrix accumulation in fibroblasts.…”

Extracellular matrix composition and interstitial pH modulate NHE1-mediated melanoma cell motility

“…62). Spontaneous metastasis of breast cancer to lung and bone is enhanced by α ν β 3 integrins, partially due to their strong binding to fibronectin and vitronectin (63)(64)(65). In addition, binding of α ν β 3 integrins to ECM proteins prevents apoptosis in a foreign environment (66).…”

Bone composition: relationship to bone fragility and anti-osteoporotic drug effects

“…37 Studies with a variety of different conditional knockout animals demonstrated that while osteoblasts produce fibronectin, they are not responsible for the presence of the same in the bone extracellular matrix; rather, the bone matrix fibronectin is derived from circulating liver fibronectin. 38 In primary biliary cirrhosis, the incidence of osteoporosis is markedly elevated. This higher incidence is due to an increased production of a fibronectin isoform that lessens osteoblastic bone formation.…”