Lecture 6 Flashcards
Bone remodelling: resorption (breakdown) of bone
Bone resorption = activity of osteoclasts
- normally active on <1% of bone surface
- osteoclast expression of RANK (RANKL receptor) is stimulated by M-CSF therefore, no M-CSF expression = no RANK expression and no osteoclast activity
Mechanism:
- osteoclast send out villus like projections towards bone which form the ruffled border: increases SA of cell membrane that’s in contact with the bone surface
- they then secrete proteolytic enzymes (Cathespin K) stored in lysosomes to digest organic matrix of the bone (type 1 collagen, osteonectin, osteocalcin,etc)
- secrete citric acid to dissolve hydroxyapatite and help digest bone matrix which releases free calcium and phosphorus
Osteoclast activity in bone resorption (diagram) mechanism
Osteoclast surface receptors: RANK or cytokine receptors (IL-6R, TNFR), calcitonin receptor -> decide on activity of osteoclast
- ruffle border formed to increase SA of membrane
- Edges of the osteoclast are sealed against the bone surface (to direct the proteolytic enzymes) through two interactions:
- integrin : expressed by osteoclast
- vitronectin: expressed on bone surface - Lysosomes (secretary vesicles) release citric acid: acidification of bone matrix dissolves hydroxyapatite (bone salts) which frees calcium and phosphorus
- Proteolytic enzymes (cathespin K) will degrade the bone matrix (type 1 collagen)
- freed calcium and phosphorus released from bone into blood (some absorbed back into bone micro environment)
- some collagen fragments absorbed back into bone micro evident but wont rly go into blood - Secretion of TRAP proteins help break the connection between integrin and vitronectin to allow osteoclast to move along the bone surface and continue breaking down
- keeps going until stopped by calcitonin surface receptor
Factors affecting bone turnover
- Stimulators of bone resorption:
- inflammatory cytokines (TNFa, IL-6)
- lipid mediators, growth factors
- RANK-L bound to RANK
- PTH - Inhibitors of bone resorption:
- cytokines: IL-4, IFNy)
- calcitonin - Stimulators of bone formation
- insulin like growth factors (IGFs)
- ESTROGEN
Osteoporosis reminders (review)
Systematic skeletal disease characterized by low bone mineral density (BMD) and micro architectural deterioration of bone tissue
Results in increased risk of fractures - no symptoms prior
Dual X-ray (DXA or DEXA) most important determinant of bone strength used clinically
Incidence of fracture with age
- increase with age
- vertebral fractures higher than hip fracture because its made up of more spongy bone that breaks down easier
- prevalence of osteroporotic fractures are just as common as heart attacks
Age dependency patterns in women: changes in bone mineral density
- small net loss in premenopausal women (and men of same age) : age related decline
- larger net loss in post menopausal women (less estrogen) BUT
- there’s more bone formation in post menopausal than pre menopausal
WHY? : - after certain age women do check up on BMD with DXA screening to prevent bone loss
- also increased recommendations of calcium and vit D supplements
- drugs that stimulate bone formation are prescribed
DEXA outcome and diagnosis
Uses T scores against reference point of average BMD at 30 (peak BMD before it starts declining)
- look at where patients BMD falls within standard deviation changes from the reference mean
- more than 1 standard deviation away from mean enters the osteopenia zone
- at or more than 2.5 standard deviations away from mean enters osteoporosis zone
- early menopause and low peak BMD will cause BMD to enter osteopenia/osteoporosis zone early
Activity and BMD over life cycle
- BMD always higher in active people
- excercise has been shown to decrease pre-osteoclast activation/maturation by:
— increasing OPG secretion by the osteoblast
— decreasing RANKL expression by the osteoblast
Dietary bioactives and mechanisms to reduce bone resorption: PUFAs
ideal ratio of n-6 to n-3 PUFA = 4:1
Long chain n-6 PUFA (arachidonic acid, AA)
- precursor for inflammatory eicosanoid synthesis which DISRUPTS the balance between osteoclast and osteoblast activity by:
— decreases OPG secretion and increased RANK-L secretion from osteoblasts
— stimulates RANK expression on osteoclasts
— inhibits osteoclast apoptosis -> continued activity of mature osteoclasts
Long chain n-3 PUFA (DHA, EPA)
- increases calcium pump expression
- decreases TNF-a and IL-6 secretion (potent activators of osteoclasts)
- decrease RANKL and MCSF secretion
- increase growth factor secretion (IGF)
- precursor for non inflammatory eicosanoids
More n-3 PUFA than n-6 PUFA better for bone health
Dietary bioactives and mechanisms to reduce bone resorption: plant polyphenols
Ex: resveratrol in grapes, catechin in tea leaves and berries
- attenuate inflammatory signalling via suppression of NFkB activation (controls TNFa)
- inhibits RANK-L secretion from osteoblasts
- stimulate OPG secretion from osteoblasts
- inhibit activation of eicosanoid synthesizing enzymes like COX-2 therefore decreasing PGE2 synthesis
- increasing RUNX2 which stimulates pre osteoblasts into osteoblasts
- upregulate growth factors
Dietary Bioactives and mechanisms to reduce bone resorption: soy isoflavones
Ex: genistein and diadzein
- function as phytoestrogens, bind to estrogen receptor
- can syngerize with vit D to increase estrogen receptor expression on osteoblasts
- stimulate 1-a-hydroxylase expression kidney
- increase OPG and osteocalcin secretion and reduce RANK-L secretion
- induce osteoclast apoptosis
- decrease inflammatory cytokines
- stimulate osteoblast maturation via upregulation of RUNX2
