Regulation of bone formation by adiponectin through autocrine/paracrine and endocrine pathways

Abstract

Since interaction between bone and lipid metabolism has been suggested, this study investigated the regulation of bone metabolism by adiponectin, a representative adipokine, by analyzing deficient and overexpressing transgenic mice. We initially confirmed that adiponectin and its receptors were expressed in osteoblastic and osteoclastic cells, indicating that adiponectin can act on bone not only through an endocrine pathway as a hormone secreted from fat tissue, but also through an autocrine/paracrine pathway. There was no abnormality in bone mass or turnover of adiponectin-deficient (Ad-/-) mice, possibly due to an equivalent balance of the two pathways. In the culture of bone marrow cells from the Ad-/- mice, osteogenesis was decreased compared to the wild-type (WT) cell culture, indicating a positive effect of endogenous adiponectin through the autocrine/paracrine pathway. To examine the endocrine action of adiponectin, we analyzed transgenic mice overexpressing adiponectin in the liver, and found no abnormality in the bone. Addition of recombinant adiponectin in cultured osteoprogenitor cells suppressed osteogenesis, suggesting that the direct action of circulating adiponectin was negative for bone formation. In the presence of insulin, however, this suppression was blunted, and adiponectin enhanced the insulin-induced phosphorylations of the main downstream molecule insulin receptor substrate-1 and Akt. These lines of results suggest three distinct adiponectin actions on bone formation: a positive action through the autocrine/paracrine pathway by locally produced adiponectin, a negative action through the direct pathway by circulating adiponectin, and a positive action through the indirect pathway by circulating adiponectin via enhancement of the insulin signaling.

Identification of gene pathways altered by deletion of the androgen receptor specifically in mineralizing osteoblasts and osteocytes in mice

“…The upregulation of Adipoq expression in bone of the mOBL-ARKOs is consistent with an action of androgens, acting via the AR in mineralizing osteoblasts to negatively regulate the expression of adiponectin. The increased Adipoq expression within bone of the mOBLARKOs together with the increased mineralization observed in these mice is also consistent with the positive actions through the autocrine/paracrine pathway of locally produced adiponectin within bone to stimulate bone formation (Berner et al 2004, Shinoda et al 2006.…”

Glucose-dependent insulinotropic polypeptide receptor deficiency leads to modifications of trabecular bone volume and quality in mice

“…Connections between fat and bone metabolism have been evidenced, with a role for adipokines in controlling bone remodeling. Adiponectin controls bone formation through paracrine and endocrine pathways [37]. Through a paracrine manner, adiponectin increases osteogenesis whilst circulating levels of adiponectin have been linked to indirectly enhancing insulin signaling in osteoblasts and as such increasing bone formation.…”

Adiponectin as a tissue regenerating hormone: more than a metabolic function

“…Primary human osteoblasts [8] and murine osteoblastic and osteoclastic cells express adiponectin and adiponectin receptors [9], thus suggesting that adiponectin can affect bone homeostasis through both endocrine and autocrine/paracrine mechanisms. Adiponectin is also produced by both human and rat…”