HLSC 2410: Growth Hormone & Parathyroid Hormone
Long Bone Anatomy and Mechanisms of Bone Growth
Bone as a Living Tissue
Bone forms the skeletal system and is a dynamic, living tissue.
Anatomy:
Epiphyses: The ends of a long bone.
Diaphysis (Shaft): The middle section of a long bone.
Epiphyseal Growth Plate:
Located between the epiphysis and diaphysis.
Consists of actively proliferating cartilage.
Deposits material crucial for bone growth.
Cellular Components in Bone Growth:
Chondrocytes: Facilitate active cartilage growth by providing new cartilage material. They continue to function until puberty.
Osteoblasts: Bone-forming cells. Their primary role is to mineralize the growth plate, effectively converting cartilage into bone. They build bone.
Osteocytes: Mature bone cells embedded within the bone matrix. They sense mechanical pressure and contribute to bone remodeling, ultimately maintaining bone structure.
Osteoclasts: Bone-resorbing cells. They break down bone tissue to increase the availability of $\text{Ca}^{2+}$ in the bloodstream. They break down bone.
Bone Remodeling:
The entire adult skeleton undergoes a continuous remodeling process, with the entire skeleton being replaced approximately once every years.
Process: Osteoclasts dig a "cutting cone" through old bone, followed by osteoblasts which lay down new osteoid (unmineralized bone matrix) to form a new osteon.
Influence of Long Bone Growth:
Growth of various organs (brain, bone, reproductive organs) completes at different ages.
Hormonal Influences on Growth
Hormones Most Important for Human Growth:
Positive Regulators (increase growth):
Growth Hormone (GH)
Insulin-Like Growth Factors-1 & 2 (IGF-1 & 2)
Thyroid Hormones (specifically $\text{T}_{3}$)
Insulin
Sex Hormones (Estrogen & Testosterone)
Negative Regulator (decrease growth):
Cortisol
Negative Feedback Mechanism:
A control system where the response changes the variable in the opposite direction of the initiating stimulus.
General Principle: Gland 1 produces Hormone 1. Hormone 1 stimulates Gland 2 to produce Hormone 2. Hormone 2 then suppresses the production of Hormone 1 from Gland 1, bringing the system back to balance.
Hypothalamic-Pituitary-Somatic (HPS) Axis
Components and Regulation:
Hypothalamus: Produces Growth Hormone-Releasing Hormone (GHRH).
Anterior Pituitary: $\text{GHRH}$ stimulates "Somatotrophs" in the anterior pituitary to secrete Growth Hormone (GH).
Liver: $\text{GH}$ acts on the liver to stimulate the production and secretion of Insulin-Like Growth Factor-1 (IGF-1).
Negative Feedback: Elevated $\text{IGF-1}$ levels provide negative feedback, suppressing the production of $\text{GH}$ by the anterior pituitary and $\text{GHRH}$ by the hypothalamus. This reduces $\text{IGF-1}$ levels back towards normal.
Balance of GH Synthesis & Release from Anterior Pituitary Somatotrophs:
Stimulatory: $\text{GHRH}$ binds to its receptor on somatotrophs, stimulating $\text{GH}$ synthesis and release.
Inhibitory: Somatostatin (SST) binds to its receptor on somatotrophs, inhibiting $\text{GH}$ synthesis and release.
Anti-Insulin Effects of Growth Hormone (GH)
Overall Effect: Increases blood glucose levels (hyperglycemia).
Mechanisms on Target Tissues:
Liver: Stimulates gluconeogenesis (the creation of new glucose from non-carbohydrate sources like glycerol and amino acids).
Skeletal Muscle: Decreases glucose uptake by muscle cells.
Adipose Tissue: Increases lipolysis (the breakdown of triglycerides into glycerol and fatty acids, where glycerol is then used by the liver for gluconeogenesis). Fatty acids can be used as an alternative fuel source.
Effects of Growth Hormone (GH) and IGF-1 on Growth
Liver: $\text{GH}$ significantly increases $\text{IGF-1}$ synthesis and secretion.
Skeletal Muscle:
Increases protein synthesis (from amino acids).
Leads to increased muscle growth.
Bone:
Increases protein synthesis.
Promotes increased bone remodeling.
Results in increased bone formation and overall bone mass.
Summary of Growth Hormone (GH) Effects
Anti-Insulin Effects of GH:
Stimulates gluconeogenesis (production of new glucose).
Decreases glucose uptake into cells.
Increases lipolysis (breakdown of fat for fuel).
GH Promotes Growth of Cells: Primarily achieved through Insulin-Like Growth Factor (IGF-1).
GH Stimulates Protein Synthesis: Works in conjunction with $\text{IGF-1}$.
Effects of Sex Hormones on Growth
Estrogen:
Stimulates growth during puberty, partly through its interaction with $\text{GH}$.
Crucially, it is responsible for epiphyseal (growth plate) closure, which marks the cessation of long bone growth.
Testosterone:
Stimulates growth during puberty, also through $\text{GH}$ mediation.
Causes epiphyseal closure, ending long bone growth.
Strongly stimulates protein synthesis in males in bone and other target organs, contributing to increased muscle mass compared to females.
Effects of Cortisol on Growth (Negative Regulator)
Role: Major stress hormone.
Actions on Growth:
Inhibits bone growth.
Stimulates protein catabolism (breakdown of proteins into amino acids for energy).
Inhibits $\text{GH}$ secretion.
High stress leads to $\text{HPA}$ axis activation and an increase in cortisol, negatively impacting growth.
Calcium Regulation and Homeostasis
Importance: Calcium () homeostasis is critically important and tightly regulated throughout the body.
Large deviations in extracellular $\text{Ca}^{2+}$ levels (either too high or too low) can severely disrupt neurological and muscular activity.
Hormonal Action: Hormones regulate $\text{Ca}^{2+}$ by binding to receptors at specific effector sites.
Effector Sites for $\text{Ca}^{2+}$ Homeostasis:
Bone: Acts as a storage site and source for $\text{Ca}^{2+}$ release.
Kidneys: Regulate $\text{Ca}^{2+}$ reabsorption (preventing loss in urine).
Gastrointestinal (GI) Tract: Controls $\text{Ca}^{2+}$ absorption from digested food.
Hormonal Controls for $\text{Ca}^{2+}$:
Two Major Hormones that INCREASE Plasma $\text{Ca}^{2+}$ Levels:
Parathyroid Hormone (PTH)
1,25-dihydroxyvitamin $\text{D}_{3}$ (Calcitriol, or Active Vitamin D)
Note: Calcitonin plays a minor role in humans in decreasing plasma $\text{Ca}^{2+}$ levels.
Parathyroid Hormone (PTH)
Source: Secreted by the parathyroid glands.
There are four small parathyroid glands located in the neck, typically on the posterior surface of the much larger thyroid gland.
Significance: PTH is critically important for the regulation of $\text{Ca}^{2+}$ levels.
Stimulus: Responds to low blood $\text{Ca}^{2+}$ levels.
Effects to Increase Blood $\text{Ca}^{2+}$ Levels:
Bone: Increases osteoclast activity, leading to increased bone resorption (release of $\text{Ca}^{2+}$ and phosphate from bone).
Kidneys:
Increases $\text{Ca}^{2+}$ reabsorption from the renal tubules back into the blood.
Decreases phosphate (PO$ ext{}{4}^{3-}$) reabsorption, leading to increased phosphate excretion. This is crucial because an optimal ratio of is needed for bone formation. While PTH increases both $\text{Ca}^{2+}$ and phosphate release from bone, it specifically promotes phosphate excretion by the kidneys to prevent calcium phosphate crystals from reforming in the blood, thus keeping $\text{Ca}^{2+}$ soluble and available.
Increases the formation of active Vitamin D (calcitriol) by stimulating the 1-hydroxylase enzyme in the kidneys.
GI Tract: Indirectly increases the uptake of $\text{Ca}^{2+}$ by stimulating the formation of active Vitamin D, which then acts on the $\text{GI}$ tract.
Calcitriol (Active Vitamin D; 1,25-D)
Activation Process ("Vitamin D Activation Pathway"):
Initial Sources: Dietary vitamin $\text{D}{2}$ or $\text{D}{3}$, or $\text{D}_{3}$ synthesized in the skin from 7-dehydrocholesterol upon exposure to sunlight.
Liver: Vitamin D ($\text{D}_{3}$) is converted to 25-hydroxyvitamin D (25-OH D) by the enzyme 25-hydroxylase.
Kidneys: 25-OH D is further converted to 1,25-dihydroxyvitamin D (1,25-D or Calcitriol), the active form, by the enzyme 1-hydroxylase. This step is strongly stimulated by PTH, especially in response to low blood $\text{Ca}^{2+}$.
Effect on Blood $\text{Ca}^{2+}$ Levels: Increases blood $\text{Ca}^{2+}$ levels.
Mechanism:
Mainly acts on the $\text{GI}$ tract.
Increases the gene expression of $\text{Ca}^{2+}$ and PO$ ext{}_{4}^{3-}$ transporters in the intestinal cells.
Results in increased absorption of both $\text{Ca}^{2+}$ and PO$ ext{}_{4}^{3-}$ from food into the bloodstream.
Clinical Relevance: Approximately of Americans are deficient in Vitamin D. Individuals living above the parallel are at higher risk due to less sunlight exposure. Vitamin D is crucial for healthy bones and can impact mood (e.g., Seasonal Affective Disorder, SAD).
Calcitonin
Source: Secreted by the parafollicular cells (C cells) of the thyroid gland.
Stimulus: Only stimulated by very high plasma $\text{Ca}^{2+}$ levels.
Effect on Blood $\text{Ca}^{2+}$ Levels: Decreases plasma $\text{Ca}^{2+}$ concentration.
Mechanisms:
Inhibits osteoclast activity, thereby reducing bone resorption and $\text{Ca}^{2+}$ release from bone.
Promotes bone deposition by activating osteoblasts, facilitating $\text{Ca}^{2+}$ uptake into bone.
Hormones Regulating Bone & Calcium Interaction Summary
Hormones that Increase Bone Formation & Increased Bone Mass:
Insulin
Growth Hormone (GH)
Insulin-like Growth Factor 1 (IGF-1)
Estrogen
Testosterone
Calcitonin
Hormones that Primarily Increase Bone Resorption & Can Lead to Decreased Bone Mass (Especially under chronic or excessive conditions):
Parathyroid Hormone (PTH)
Cortisol