The GH/IGF-1 axis

The GH/IGF-1 axis

Hypothalamic growth hormone (GH) releasing hormone (GHRH) and somatostatin (SST) stimulate or inhibit pituitary GH secretion, respectively. GH reaches target tissues, binds its widely expressed GH receptor (GHR), and transduces cellular signals to promote cellular growth, differentiation, and function.

In liver, activation of the GH leads to transcription and secretion of the insulin-like growth factors 1 and 2 (IGF-1, IGF-2), IGF-binding proteins (IGFBPs), and the acid labile subunit (ALS). The IGFBPs and the ALS stabilize the IGFs in the vasculature while delivered to the target tissues. Liver-derived IGF-1 contributes to 75% of serum IGF-1 pool, and provides negative feedback to pituitary GH production. IGF-1 is produced by all tissues and plays significant roles in organ function and response to tissue injury.

GH/IGF regulate fat metabolism, muscle mass and strength, linear bone growth, and bone mineral acquisition. In the extracellular compartments of most tissues, IGFBP-proteases cleave the IGFBPs and release IGFs to bind to its receptor. 

Germline Mutation in Genes Associated with the GH/IGF-1 AXIS

Germline mutations identified in humans

Several germline mutations in genes encoding components of the GH/IGF-1 axis, were identified in humans.

Regulation of Skeletal Acquisition by the GF/IGF-1 AXIS

Bone-cell specific effects

Regulation of skeletal acquisition and maintenance by the GH/IGF-1 axis: Overwhelming evidence exists to implicate GH/IGF-1 in the regulation of bone growth and development. In mouse developmental studies, regulation of long bone length is very clear and is supported by changes in the proliferative and hypertrophic zones of the growth plate. Postnatal changes in cortical and cancellous bone properties are also well established in conjunction with changes in IGF-1 levels. GH/IGF-1 act on mesenchymal stem cells and participate in regulation of the progenitor pool of the osteogenic lineage. IGF-1 regulates matrix deposition and mineralization via its effects on osteoblasts, osteocytes and osteoclasts.

Animal Models of the GH/IGF-1 axis

Animal Models of the GH/IGF

Animal models, characterized in the Yakar Lab: our understanding of the GH–IGF-1 axis and how it affects skeletal development is largely based on work in animal experimental systems. With the development of transgenic and knockout techniques, it is now clear that mutations in components of the GH–IGF-1 axis result in growth retardation and numerous skeletal phenotypes.

Osteocytes, The Bone Resident Cells

Osteocytes are abundant cells in bone

Osteocytes are the most abundant cells in bon (>95%). These cells are embedded in the mineralized matrix and are connected via lacunar-canalicular system (LCS). Below is a confocal Z-stack of cortical bone (femur) representing the LCS.

Yakar Lab: Osteocytes


Somatopause Effects on The Aging Bone

Yakar Lab: Aged Bone Control

Yakar Lab: Aged Bone Somatopause-induced

The aging bone: In the developing world chronic diseases are the main causes of mortality and morbidity in old age. With the increase in the elderly population we expect to see more people with senile osteoporosis (age-induced bone loss), and fractured hips. During aging the somatotropic-signals of the GH/IGF-1 decline, a state termed somatopause. Somatopause has been considered a significant cause for changes in body composition, BMD, as well as increased morbidity and mortality. We have generated a unique mouse model of age-induced somatopause that unlike the congenital models does not exhibit changes in body weight, body composition, glucose or insulin sensitivities, but shows severe morphological and compositional bone changes.