J Bone Metab.  2014 Feb;21(1):41-54.

Role of Osteocyte-derived Insulin-Like Growth Factor I in Developmental Growth, Modeling, Remodeling, and Regeneration of the Bone

• Sheng MH
• Lau KH
• Baylink DJ

Abstract

The osteocyte has long been considered to be the primary mechanosensory cell in the bone. Recent evidence has emerged that the osteocyte is also a key regulator of various bone and mineral metabolism and that its regulatory effects are in part mediated through locally produced osteocyte-derived factors, such as sclerostin, receptor activator of nuclear factor-kappa B ligand (RANKL), and fibroblast growth factor (FGF)-23. Osteocytes secrete large amounts of insulin-like growth factor (IGF)-I in bone. Although IGF-I produced locally by other bone cells, such as osteoblasts and chondrocytes, has been shown to play important regulatory roles in bone turnover and developmental bone growth, the functional role of osteocyte-derived IGF-I in the bone and mineral metabolism has not been investigated and remains unclear. However, results of recent studies in osteocyte Igf1 conditional knockout transgenic mice have suggested potential regulatory roles of osteocyte-derived IGF-I in various aspects of bone and mineral metabolism. In this review, evidence supporting a regulatory role for osteocyte-derived IGF-I in the osteogenic response to mechanical loading, the developmental bone growth, the bone response to dietary calcium depletion and repletion, and in fracture repair is discussed. A potential coordinated regulatory relationship between the effect of osteocyte-derived IGF-I on bone size and the internal organ size is also proposed.

Keyword

Bone regeneration; Bone remodeling; Fracture healing; Insulin-like growth factor I; Osteocytes

MeSH Terms

Animals
Bone Development
Bone Regeneration
Bone Remodeling
Calcium, Dietary
Chondrocytes
Fibroblast Growth Factors
Fracture Healing
Insulin-Like Growth Factor I*
Metabolism
Mice
Mice, Transgenic
Organ Size
Osteoblasts
Osteocytes
RANK Ligand
Regeneration*
Calcium, Dietary
Fibroblast Growth Factors
Insulin-Like Growth Factor I
RANK Ligand

Figure

• 

  Fig. 1 A proposed molecular model for the role of osteocyte-derived insulin-like growth factor-I (IGF-I) in the mechanotransduction between osteocytes and osteoblasts. SOST, sclerostin; Cox2, cyclooxygenase-2; PGE2, prostaglandin E2; IGF-I, insulin-like growth factor-I. [Modified from "Osteocyte-derived insulin-like growth factor I is essential for determining bone mechanosensitivity", by Lau KH, Baylink DJ, Zhou XD, Rodriguez D, Bonewald LF, Li Z, Ruffoni D, Müller R, Kesavan C, Sheng MH, 2013, Am J Physiol Endocrinol Metab, 305(2), pp. E271-81. Copyright 2013 by the The American Physiological Society. Reprinted with permission].

• 

  Fig. 2 The conditional disruption of the Igf1 gene in osteocytes had contrasting effects on the bone formation response (i.e., the relative endosteal bone formation rate) to a two-week loading regimen in the form of 4-point-bending exercise at the tibia and on the bone formation response to the one-week of dietary calcium repletion that followed a two-week dietary calcium restriction. WT, wild-type; KO, knockout.

• 

  Fig. 3 The phenotype of smaller bone size in osteocyte Igf1 conditional knockout (KO) mice persists with age and no evidence for catch-up growth. To determine the age effect of targeted disruption of the Igf1 gene in osteocytes on the bone size, body weight (left panel) and various parameters of bone size, i.e., femur length (middle panel) and periosteal circumference at the mid-shaft of femur (right panel), of female KO mice of various age, ranging from 4 to 16 weeks of age, were determined and compared with those of corresponding age-and sex-matched wild-type (WT) littermate mice (n=5-14 per group). Results are shown as mean±SEM. *P<0.05. **P<0.001 vs. WT littermates, by two-tailed Student's t-test.

• 

  Fig. 4 A significant reduction in the size of vital internal organ was detected in female osteocyte Igf1 conditional KO mice during developmental growth and in adulthood compared to age- and sex-matched wild-type (WT) littermates (n=5-14). The wet weight of various internal organs, e.g., kidney (left panel), liver (right panel), and spleen (not shown), of conditional knockout (KO) mice and corresponding WT littermate mice at the ages of 4-16 weeks was measured. Results are shown as mean±standard error of the mean (SEM). *P<0.05 vs. WT littermates.

• 

  Fig. 5 The kidney weight of the mouse correlates with the parameters of the femur size (periosteal bone circumference [Peri. Cir., middle panel] and bone length [right panel]) or body weight (left panel) of mice. WT littermates: blue squares, and osteocyte Igf1 conditional KO mice: red triangles.

• 

  Fig. 6 A proposed model for osteocyte-mediated endocrine regulation of internal organ size. It is postulated that osteocytes produce insulin-like growth factor-I (IGF-I) locally to regulate bone size during developmental growth. Osteocytes, either independently or upon stimulation by osteocyte-derived IGF-I, produce a putative endocrine agent, which we tentatively called it as the "Scalotrophin". This putative "Scalotrophin" is then secreted into the circulation and travels to sites of internal organs, such as kidney, liver, and spleen, to mediate the proportional growth in size of these internal organs.

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