Osteocyte-derived insulin-like growth factor I is essential for determining bone mechanosensitivity

Abstract

This study sought to determine whether deficient Igf1 expression in osteocytes would affect loading-induced osteogenic response. Tibias of osteocyte Igf1 conditional knockout (KO) mice (generated by cross-breeding Igf1 floxed mice with Dmp1-Cre transgenic mice) and wild-type (WT) littermates were subjected to four-point bending for 2 wk. Microcomputed tomography confirmed that the size of tibias of conditional mutants was smaller. Loading with an equivalent loading strain increased periosteal woven bone and endosteal lamellar bone formation in WT mice but not in conditional KO mice. Consistent with the lack of an osteogenic response, the loading failed to upregulate expression of early mechanoresponsive genes (Igf1, Cox-2, c-fos) or osteogenic genes (Cbfa-1, and osteocalcin) in conditional KO bones. The lack of osteogenic response was not due to reduced osteocyte density or insufficient loading strain. Deficient osteocyte Igf1 expression reduced the loading-induced upregulation of expression of canonical Wnt signaling genes (Wnt10b, Lrp5, Dkk1, sFrp2). The loading also reduced (by 40%) Sost expression in WT mice, but the loading not only did not reduce but upregulated (~1.5-fold) Sost expression in conditional KO mice. Conditional disruption of Igf1 in osteocytes also abolished the loading-induced increase in the bone β-catenin protein level. These findings suggest an impaired response in the loading-induced upregulation of the Wnt signaling in conditional KO mice. In summary, conditional disruption of Igf1 in osteocytes abolished the loading-induced activation of the Wnt signaling and the corresponding osteogenic response. In conclusion, osteocyte-derived IGF-I plays a key determining role in bone mechanosensitivity.

Sclerostin's role in bone's adaptive response to mechanical loading

“…However, once sclerostin had been shown to be expressed in osteocytes [9], Robling et al [16] convincingly demonstrated that one potentially important mechanism by which mechanical loading controls osteocyte activity is by regulating sclerostin expression. His demonstration that loading the mouse ulna down regulates sclerostin expression has been reproduced in a variety of experimental loading models [17], [18], [19], [20], [21], [22], [23] (Fig. 1).…”

“…For example, increased basal sclerostin expression, abrogation of sclerostin down-regulation with loading and reduced load-related bone formation is observed in periostin knockout (Postn −/− ) mice [22]. Similarly, four point tibial bending of mice lacking osteocytic Igf1 expression does not result in Sost down-regulation and triggers a diminished osteogenic response to loading compared with wild type controls [23]. In contrast, deletion of the androgen receptor in male androgen receptor (AR) knockout mice is associated with greater sclerostin down-regulation and enhanced bone formation following loading compared with wild type controls [21].…”

Skeletal effects of growth hormone and insulin-like growth factor-I therapy

“…More recently, the link between IGF-I upregulation and bone formation in response to mechanical loading has been more definitively demonstrated through the use of conditional IGF-I gene disruption in mouse osteoblasts expressing type 1α collagen (Kesavan et al, 2011). Osteocyte-derived IGF-I has also been shown to be a key determinant in bone mechanosensitivity, as well as bone growth, remodeling, and regeneration (Lau et al, 2013; Sheng et al, 2014), although it is not required for bone repletion after a low-calcium challenge (Lau et al, 2015). Regulation of IGF-I expression is critically important and is accomplished a multitude of diverse systemic and local factors and their interactions.…”

Serum sclerostin decreases following 12months of resistance- or jump-training in men with low bone mass

“…That is, systemic and paracrine hormonal factors modulate osteocyte mechanotransduction and osteoblast response, thereby influencing local bone re(modeling) at the site of augmented mechanical strain. For example, insulin-like growth factor-I (IGF-I) plays an important role in the early stages of the osteoblast adaptive response to mechanical loading [14–17]. IGF-I is locally expressed in osteoblasts and osteocytes [18], but circulating IGF-I is increased by hepatic expression and IGF-I released from skeletal muscle has paracrine effects [19].…”