Altered bone development and turnover in transgenic mice over‐expressing Lipocalin‐2 in bone

Abstract

Lipocalin-2 (LCN2) is a protein largely expressed in many tissues, associated with different biological phenomena such as cellular differentiation, inflammation and cancer acting as a survival/apoptotic signal. We found that LCN2 was expressed during osteoblast differentiation and we generated transgenic (Tg) mice over-expressing LCN2 in bone. Tg mice were smaller and presented bone microarchitectural changes in both endochondral and intramembranous bones. In particular, Tg bones displayed a thinner layer of cortical bone and a decreased trabecular number. Osteoblast bone matrix deposition was reduced and osteoblast differentiation was slowed-down. Differences were also observed in the growth plate of young transgenic mice where chondrocyte displayed a more immature phenotype and a lower proliferation rate. In bone marrow cell cultures from transgenic mice, the number of osteoclast progenitors was increased whereas in vivo it was increased the number of mature osteoclasts expressing tartrate-resistant acid phosphatase (TRAP). Finally, while osteoprotegerin (OPG) levels remained unchanged, the expression of the conventional receptor activator of nuclear factor-κB ligand (RANKL) and of the IL-6 was enhanced in Tg mice. In conclusion, we found that LCN2 plays a role in bone development and turnover having both a negative effect on bone formation, by affecting growth plate development and interfering with osteoblast differentiation, and a positive effect on bone resorption by enhancing osteoclast compartment.

Lipocalin-2 inhibits osteoclast formation by suppressing the proliferation and differentiation of osteoclast lineage cells

“…In the bone, LCN2 expression is detected in chondrocytes during embryonic development [38] and induced during osteoblast differentiation [31]. In this study, we observed that LCN2 is expressed in osteoclast lineage cells and that its expression is regulated during osteoclast development.…”

“…Using transgenic mice that specifically overexpress LCN2 in osteoblasts, Costa et al reported that LCN2 negatively regulates bone development and formation by affecting growth plate development and attenuating osteoblast differentiation [31]. More recently, Rucci et al identified LCN2 as a novel osteoblast mechanoresponding gene that modulates bone homeostasis [39].…”

“…LCN2 is expressed in various tissues, including uterus, bone marrow, immune cells, adipocytes, and malignant tumors [17,[26][27][28][29][30]. Recently, Costa et al reported that LCN2 expression is also detected in bone-forming osteoblasts [31]. Employing transgenic mice overexpressing LCN2 in osteoblasts, this group further showed that LCN2 is involved in skeletal development and osteoblast differentiation.…”

Podwyższone stężenia lipokaliny-2 w surowicy krwi są związane ze wskaźnikami metabolizmu glukozy i metabolizmu kostnego w przebiegu cukrzycy typu 2

“…A study by Costa et al indicated that osteoblasts in mice expressed LCN2. Moreover, their study suggested that LCN2 exerted both a negative effect on bone formation and a positive effect on bone resorption [8]. Another study supported the role of LCN2 in inducing bone loss [9].…”

“…Emerging evidence has revealed the association of LCN2 with bone. Costa et al found that transgenic mice over-expressing LCN2 in bone displayed bone micro-architectural changes and reduced bone mass, including a thinner layer of cortical bone and a decreased trabecular number [8]. LCN2 was also shown to reduce osteoblast differentiation and be involved in osteoblast-osteoclast coupling [8,9].…”