4/20/2009. From: Ham, AW & Cormack, DH Ham s Histology. Lippincott, Philadelphia.

Transcription

1 Bone: regulation of development and growth Bone Modeling From: Ham, AW & Cormack, DH Ham s Histology. Lippincott, Philadelphia. 1

2 Bone Remodeling Removal of damaged/aged bone by osteoclasts t (microdamage) Replacement with new bone by osteoblasts (that become osteocytes) Process is linked: resorption followed by deposition (keeps bone strong) Cell responsible for resorption: Osteoclast From: Gerrard, DE & Grant, AL Principles of Animal Growth & Development. Kendall/Hunt Pub. Co., Dubuque, IA 2

3 From: Gerrard, DE & Grant, AL Principles of Animal Growth & Development. Kendall/Hunt Pub. Co., Dubuque, IA An osteoclast in action Osteoclasts act to degrade bone. Here an osteoclasts is eroding bone. The hollow formed by such action is called a Howship's lacunae (H). Similar to the cell of the gut, osteoclasts have a ruffled border which increases the surface area for bone resorption. (Image adapted from Color Atlas of Basic Histology, Ed. I. Berman, Appleton & Lange, 1993) 3

4 Intramembranous bone formation Occurs without a cartilage model (i.e., within a membrane only); Under high po 2, relatively undifferentiated mesenchymal cells become osteoblasts, and surround themselves with osteoid, which is then calcified (sound familiar?); Bone growth occurs by apposition. Examples: Flat bones Skull Chin Digits From: Gerrard, DE & Grant, A Co., Dubuque, IA evelopment. Kendall/Hunt Pub. AL Principles of Animal Growth & De 4

5 Intramembranous bone formation 1. In intramembranous bone formation, mesenchymal cells migrate to the site of eventual bone formation 2. Cells condense, align and secrete an organic framework of extracellular matrix (ECM), i.e. the osteoid (or ground substance) 3. Cells continue to proliferate during the entire osteogenic process 4. The osteoid is laid down in long strands 5. Osteoblasts (differentiated mesenchymal cells) line the osteoid and begin to deposit calcium salts, (i.e., mineralization phase) forming bony trabeculae 6. Consecutive growth rings added to the trabecula to increase thickness: lamellae are added by cycles of osteoid secretion and mineralization (appositional growth) Intramembranous bone formation. Note: no cartilage cores CM=condensed mesenchyme M=mesenchyme O=osteoblasts BL= trabeculae of bone V=blood vessels BL=bone-lining cells OB=osteoblasts CL=cement line (boundary line) O=osteocytes V=blood vessels (Images adapted from Color Atlas of Basic Histology, Ed. I. Berman, Appleton & Lange, 1993) 5

6 Wt or length, % of bir rth 100 Length Weight Trimester Bone is an earlymaturing tissue, and is relatively resistant to nutritional or other restriction, therefore, body length (crownrump) is often used as an indicator of fetal age. Physical factors affecting bone Tissue interactions fetal development of bone, muscle, tendons, etc. simultaneous; Tendons insert into developing cartilage model; Bone protuberances guided by insertions, forces acting upon bone; e.g., tenotomy: muscle atrophies, bone continues to grow; cartilage removal: muscles & tendons disappear 6

7 Effects of tension 1. The periosteum is attached to the bone (firmly) at the epiphyses and (loosely) at the diaphysis; 2. As the bone elongates, the periosteum is stretched, t creating tension on the periosteum; Effects of tension 3. The periosteum responds to the increased tension by ing its rate of cell proliferation; 4. This proceeds until it overshoots bone length, decreasing the tension on the bone; 5. The growth plate responds to the reduced tension by ing its rate of proliferation and ossification, which elongates the bone and starts the entire cycle over again. 7

8 Effects of tension There is an optimal tension for bone growth and maintenance; this is related to the presence of an electrical current (e.g., fracture repair, electric blankets, high-voltage power lines) If periosteal attachments are severed, growth plate proliferation is very rapid; Similarly, if one GP is damaged or closes prematurely, the other GP may compensate by more rapid proliferation. Post-natal growth Growth plate closure puts a stop to linear growth (depends upon age, species, breed, anatomical location); Crocodiles & alligators: GPs never close; No general rule (proximal vs.distal); No single event (GP closures occur over several years); Therefore, there are local regulators at each GP, although these are likely influenced by systemic factors and events (e.g. puberty). 8

9 Post-natal growth First major regulator identified: growth hormone (1920 s-30 s) Hypophysectomy (hypox) removal of anterior pituitary No further bone elongation Narrower GPs no proliferative & hypertrophic zones GH replacement GP widens, growth is near-normal GH stimulates bone growth, BUT: chondrocytes in vitro did not respond to GH somatomedin hypothesis: Anterior pituitary GH Liver IGF-I Growth plate 9

10 Evidence against the somatomedin hypothesis Infusion of GH into the growth plate of hypox rats increases GP width compared to the contralateral GP, the GH effect is also local Infusion of IGF-I is also effective GH is ineffective if IGF-I is blocked by a specific antibody Almost all tissues express mrna for IGF-I (including chondrocytes) Dual Effector Theory Circulating GH primes the growth plate to respond to IGF-I Circulating GH also stimulates proliferative zone chondrocytes to produce IGF-I Locally produced (paracrine) IGF-I stimulates chondrocyte proliferation and hypertrophy From: Davis, SL Recent concepts in the regulation of growth by GH and IGF. Journal of Animal Science 66 (Suppl. 3):

11 Abnormalities of GH function Giants: excess GH prior to growth plate closure wider proliferative zone delayed GP closure Acromegaly: excess GH after growth plate closure growth by apposition only affects mainly the cranium, digits, feet (disproportionate) Dwarfism: several types, including hypopituitary (low GH) Laron (high [GH] but low IGF-I) pygmies (normal GH and IGF-I, but tissues unresponsive) hypothyroid Single IGF1 Allele Is a Major Determinant of Small Size in Dogs (Science 6 April 2007) The domestic dog exhibits greater diversity in body size than any other terrestrial vertebrate We used a strategy that vertebrate. exploits the breed structure of dogs to investigate the genetic basis of size. First, through a genome-wide scan, we identified a major quantitative trait locus (QTL) on chromosome 15 influencing size variation within a single breed. Second, we examined genetic variation in the 15- megabase interval surrounding the QTL in small and giant breeds and found marked evidence for a selective sweep spanning a single gene (IGF1), encoding insulin-like growth factor 1. A single IGF1 single- nucleotide polymorphism haplotype is common to all small breeds and nearly absent from giant breeds, suggesting that the same causal sequence variant is a major contributor to body size in all small dogs. 11

12 Thyroid hormone Marked growth reduction in all hypothyroid animals Little data on direct effects in bone Increases width of growth plate ( recruitment of resting chondrocytes) From: Ganong, WF Review of Medical Physiology. Lange Medical Publications, Los Altos, CA. 12

13 Glucocorticoids Direct effects: chondrogenesis Indirect effects: GH secretion by pituitary, GP mrna for GHR, GHBP, IGF-I, IGF-IR Sex steroids Pubertal growth spurt accounts for ~20% of adult height (growth spurt lasts ~ 22 months) Pubertal growth spurt due mainly to estrogen and testosterone (testosterone converted to estrogen) 13

14 From: van der Eeerden et al., Endocrine Reviews 24: 872. Sex steroids Effect the GH/IGF-I axis: at puberty sex steroids, primarily estrogen, increase GH pulsatility (rate & amt per pulse) and thereby increases IGF-I Female estrogen GH at younger ages than male testosterone does Estrogen alters growth plate activity chondrocytes have genomic and non genomic receptors Lack of estrogen is involved in the post-menopausal onset of osteoporosis; excess bone loss 14

15 Testosterone Stimulates GP cell proliferation (low doses) Enhances maturation of GP, accelerates e ates closure (high doses) GH is required for its actions Acts mainly through conversion to estrogen Male ER(αR) deficient mutant: no GP fusion, severe osteoporosis; not responsive to E therapy Male CYP10 gene mutants: lack aromatase P450; similar effects, but are responsive to E Estrogen ERα and ERβ both present in GP Inhibit cartilage growth and enhance maturation of fthe GP; Low levels stimulate chondrocytes & osteoblasts indirectly (via IGF-I) High levels (e.g., at puberty) inhibit growth: cartilage growth; proliferative zone activity maturation of the GP Inhibit bone resorption by osteoclasts (thereby bone density) 15

16 Growth factor Osteoblast Osteoclast DNA Collagen resorption Insulin-like growth factor-i (IGF-I) IGF-II + + Prostaglandins Epidermal growth factor (EGF) Transforming growth factor-α (TGFα) + TGF-β Platelet-derived growth factor (PDGF) Fibroblast growth factor (FGF α, β) ++ - Interleukin-1 (IL-1 α, β) Tumor necrosis factor (TNF) - Interferon-γ Bone morphogenetic protein (BMP) + + Regulation of calcium and phosphorus All tissues/cells require precise concentrations of Ca 2+ for proper function Circulating Ca 2+ exchanges with tissue pools and the storage pool in bone 99% of body calcium (ca. 1 kg) is in the mineralized bone 16

17 Parathyroid hormone (PTH) Principal role = maintenance of plasma calcium concentration Released by the parathyroid gland in response to low plasma [Ca 2+ ]; undergoes further processing in the liver Raises plasma Ca 2+ by stimulation of: bone resorption by osteoclasts renal tubule reabsorption of calcium 1-25-(OH) 2 D3 production increased intestinal Ca 2+ absorption, bone resorption Lowers plasma P by stimulation of renal excretion, thus preventing harmful CaPO 4 precipitates in tissues PTH may be anabolic or catabolic, depending upon its interactions with other hormones and health/disease state Vitamin D (calcitriol) Nutrient and hormone Helps to maintain normal plasma calcium resorption of bone by osteoclasts intestinal absorption of Ca and P renal retention of PO 4 Direct effects on osteoblasts collagen synthesis osteocalcin synthesis IGF-I synthesis? osteoblast proliferation 17

18 Calcitonin Produced in the C cells of the thyroid gland Decreases bone resorption (direct effects on osteoclasts) 18