5. BONE BIOLOGY Flashcards
the SKELETON makes up approximately how much of our BODY WEIGHT
17%
4 FUNCTIONS of BONE
- SUPPORT of the body
- PREOTECTION of ORGANS
- Site for HAEMATOPOIESIS (blood cells from bone marrow)
- Regulation for MINERAL HOMEOSTASIS
2 STRUCTURES in BONE
- CORTICAL / CORTEX BONE
outer, compact (no gaps) - TRABECULAR BONE
gaps filled with bone marrow
CELLS of BONE (3)
- OSTEOBLASTS : MAKE bone
- OSTEOCLASTS : RESORB bone
- OSTEOCYTES : final, inactive form of Osteoblasts, most abundant, embedded in Bone Matrix, MECHANOSENSOR CELL
which CELL type is the MOST ABUNDANT in BONE
OSTEOCYTES
OSTEOBLASTS ORIGIN
MESENCHYMAL CELLS
OSTEOBLASTS express HIGH LEVELS of which ENZYME
ALKALINE PHOSPHATASE
OSTEOBLASTS SECRETE and RESPOND to many…
CYTOKINES and GROWTH FACTORS
where are OSTEOBLASTS - active or inactive (flattened)
COVER MOST BONE SURFACES
what do OSTEOBLASTS SECRETE/form
OSTEOID - UNCALCIFIED BONE MATRIX
- becomes MINERALISED/CALCIFIED
-> CALCIFIED BONE MATRIX
after SECRETING BONE MATRIX, OSTEOBLASTS BECOME
OSTEOCYTES embedded in MATRIX
have CELL PROCESSES that form huge networks into bone tissue
DIFFERENTIATION of MESENCHYMAL PROGENITOR to OSTEOBLAST is regulated by
TRANSCRIPTION FACTORS:
SOX9+
RUNX2+
RUNX2+ OSX+
SOX9+ TRANSCRIPTION FACTOR can also cause DIFFERENTIATION of MESENCHYMAL PROGENITORS into… (besides OSTEOBLASTS)
CHONDROCYTES
- become HYPERTROPHIC CHONDROCYTES
what can MESENCHYMAL PROGENITORS also become
(besides osteoblasts, chondrocytes)
ADIPOCYTE
BONE ORGANIC COMPONENT is 90%…
TYPE 1 COLLAGEN
(produced by osteoblasts)
why is bone 90% TYPE 1 COLLAGEN (what is it)
- STRUCTURAL PROTEIN providing STRENGTH, FLEXIBILITY
- MAJOR Structural Protein in the body
- also present in Tendon, Ligaments, Skin, Scar Tissue
REMAINING 10% of BONE ORGANIC COMPONENT is a COMPLEX MIXTURE of: (5)
- GROWTH FACTORS
- OSTEOCALCIN (secreted by osteoblasts, marker of bone formation)
- OSTEONECTIN
- OSTEOPONTIN
- GLYCOPROTEINS
COLLAGEN SYNTHESIS from which 2 GENES and what do they ENCODE
- COL1A1
encodes for ALPHA1 CHAIN - COL1A2
encodes for ALPHA2 CHAIN
stages of COLLAGEN SYNTHESIS (7)
- COL1A1 encodes for ALHPHA1 CHAIN
COL1A2 encodes for ALPHA2 CHAIN - 2x ALPHA1 CHAIN and 1X ALPHA2 CHAIN form TRIPLE HELICLE PROCOLLAGEN
- SECRETED into EXTRACELLULAR SPACE
- CLEAVAGE of N & C -TERMINAL PROPEPTIDES
form COLLAGEN MOLECULE
- CROSS LINKING (PYRINIDIUM) to STABILISE
in COLLAGEN SYNTEHSIS how do we get the PREMATURE form of COLLAGEN: TRIPLE HELICAL PROCOLLAGEN
2 ALPHA1 CHAINS
1 ALPHA2 CHAIN
combine
in COLLAGEN SYNTHESIS what happens to the TRIPLE HELICLE PROCOLLAGEN (2) to from COLLAGEN MOLECULE
SECRETED into EXTRACELLULAR SPACE
and CLEAVED at N & C - TERMINAL PROPEPTIDES
in COLLAGEN SYNTHESIS what happens to the MATURE COLLAGEN and why
PYRIDINIUM CROSS LINKING
- STABILISES
why are the PYRIDINIUM CROSS LINKS of COLLAGE useful
MARKERS for BONE RESORPTION
- as they are NOT BROKEN DOWN in RESORPTION
what is LAMELLAR versus WOVEN/PRIMARY BONE
LAMELLAR - several day DELAY before OSTEOID MINERALISES
WOVEN/PRIMARY - Matrix IMMEDIATELY MINERALISED after secretion - RAPID FORMATION
DIFFERENCE in STRUCTURES of LAMELLAR vs WOVEN bone
LAMELLAR - BONE LAMELLAE (lines)
HIGHLY ORGANISED
WOVEN - Not as well structured
SKELETON contains approx how much of the body’s CALCIUM
98%
the MINERAL COMPONENT of BONE is :
HYDROXYAPATITE
- Ca10 (PO4)6 (OH)2
calcium phosphate salt
- tiny CRYSTALS surround collagen fibres
what does BONE MINERAL COMPONENT - HYDROXYAPATITE PROVIDE
RIGIDITY & RESISTANCE to COMPRESSION
The MINERALISATION of OSTEOID DEPENDS on…
hormonally ACTIVE FORM of VITAMIN D3
VITAMIN D3 main source and EFFECTS of DEFICIENCY
main source: sunlight
-deficiency results in FAILURE TO MINERALISE
-leads to rickets in children, osteomalacia in adults
(bendy bones)
FULL MINERALISATION takes how long
SEVERAL MONTHS
where is ALKALINE PHOSPHATASE (ALP)
- EXPRESSED on SURFACE of DIFFERENTIATED OSTEOBLASTS
- RELEASED into EXTRACELLULAR FLUID and CIRCULATION
what can ALP act as
BONE FORMATION MARKER
what does ALP cause on various molecules
HYDROLYSIS
- RELEASE INORGANIC PHOSPHATE IONS (PO4 3-)
how does ALP PROMOTE MINERALISATION (2 ways)
- INCREASING LOCAL CONC. of INORGANIC PHOSPHATE IONS
- HYDROLYSING PYROPHOSPHATE - a key INHIBITOR of MINERALISATION
hydrolysis releases 2 phosphate ions (used for mineralisation)
what are OSTEOCLASTS
MULTINUCLEATE, MOTILE, BONE-RESORBING CELLS
(slide onto bone matrix, release proteolytic enzymes)
OSTEOCLASTS are formed by the FUSION of..
PROMONOCYTIC PRECURSORS
present in MARROW and CIRCULATION
what does the ‘RUFFLED BORDER’ of OSTEOCLASTS SECRETE
H+ ENZYMES
what do OSTEOCLASTS EXPRESS/SECRETE to RESORB BONE
- ‘ruffled border’ secretes H+ ENZYMES
- HIGH LEVELS of enzyme CARBONIC ANHYDRASE
for H+ GENERATION
CREATES ACIDIC MICRO ENVIRONMENT which causes DEGRADATION of HYDROXYAPATITE/BONE
what do OSTEOCLASTS EXPRESS that are GOOD MARKERS for RESORPTION
TARTRATE-RESISTANT ACID PHOSPHATASE (TRAcP)
what ACTIVATES OSTEOCLAST FORMATION
RANK-RANKL SYSTEM
what do OSTEOCLAST PRECURSURS have on their SURFACE and how does this ACTIVATE them to FORM OSTEOCLASTS
- RANK (receptor activator of NFkB)
- RANKL (RANK LIGAND) on OSTEOBLAST BINDS to RANK on OSTEOBLAST
- ACTIVATES NF kB (nuclear factor kB)
- ACTIVATION of PRECURSURE, DIFFERENTIATION to MATURE OSTEOCLAST
when there is EXCESSIVE BONE RESORPTION which PROTEIN REGULATES this and HOW
OPG - OSTEOPROTEGRIN
BINDS TO RANKL on OSTEOBLAST
PREVENTS ACTIVATION of OSTEOCLAST (RANKL cannot bind to RANK)
BONE DISEASE - OSTEOPETROSIS caused by
(aka Marble Bone Disease’)
DYSFUNCTIONAL OSTEOCLASTS (MUTATIONS)
characterised by INCREASED BONE MASS (little to no bone marrow)
INHERITED bone disease
OSTEOPETROSIS can be caused by WHICH MUTATIONS and what do these cause
- CA II MUTATIONS
inhibits CARBONIC ANHYDRASE (enzyme for H+) - TCIRG1 MUTATIONS
Deficient PROTEIN PUMP for H+ - CLCN7 MUTATIONS
no CHLORIDE CHANNEL, Cl- forms HCL for ACIDIC ENVIRONMENT - CAT K MUTATIONS
CATHEPSIN K enzyme not secreted
why do we need BONE METABOLISM
*To grow
*Respond to altered mechanical requirements
*Repair damage (macro / micro fractures)
*Maintenance (failure prevention)
*Calcium deficit
*Pathological (hyperparathyroidism, cancers..)
SKELETON is RENEWED approx every … years
7-10
what is the main SOURCE of RANKL
OSTEOCYTES
BONE REMODELLING CYCLE
4 STAGES
- QUIESCENCE
- RESORPTION:
when DAMAGE: OSTEOCLAST RECRUITMENT to site
10 DAYS - REVERSAL:
OSTEOBLASTS ACTIVATED - produce BONE MATRIX to fill area
3 MONTHS - FORMATION
MINERALISATION
Osteoblasts become OSTEOCYTES
how long does the BONE REMODELLING CYCLE take
4-6 MONTHS
how long is the RESORPTION STAGE of the BONE REMODELLING CYCLE
10 DAYS
how long is the REVERSAL STAGE of the BONE REMODELLING CYCLE (osteoblasts forming matrix)
3 MONTHS
what are BONES composed of and what do these contain that supply nutrients
OSTEONS
HAVERSIAN CANALS (houses nerve fibres and some capillaries)
what are HAVERSIAN CANALS supported by
VOLKMANN’S CANAL
what do OSTEOCYTES RESPOND to
MECHANICAL LOADING
- MECHANOSENSITIVE CELLS
OSTEOCYTES PRODUCE a wide range of factors that regulate bone cells:
- PROSTAGLANDINS
- NITRIC OXIDE (bone resorption)
- RANKL (main source)
- SCLEROSTIN (inhibits bone formation)
WHEN do OSTEOCYTES SECRETE SCLEROSTIN and what does this do
- EXCESSIVE BONE FORMATION (exceeds rate of resorption)
- INHIBITS ACTIVATION of PRE-OSTEOBLASTS to OSTEOBLASTS
therefore INHIBITS BONE FORMATION
consequence of LOSS of SCLEROSTIN
HIGH BONE MASS DISEASE
eg VAN BUCHEM disease & SCLEROSTEOSIS
Caused by SOST inactivating mutations
2 BONE RESORPTION MARKERS
- TRAcP (serum)
- CROSSLINKS - PYRINIDIUM (Serum/Urinary)
3 BONE FORMATION MARKERS
- OSTEOCALCIN (serum)
- TELOPEPTIDES (serum)
- ALP (serum)
2 most COMMON BONE DISEASES:
*Osteoporosis
Most common cause: Low E2 after MENOPAUSE (estrogen)
Main cause of bone loss: Increased bone resorption
*Paget’s disease
*Due to overactive osteoclasts
why do WOMEN have a greater DECREASE in BONE MASS DENSITY as they age
MENOPAUSE
- LOSS of ESTROGEN
REGULATION of BONE METABOLISM by: (2)
1: Systemic Regulation by HORMONES
2: Regulation by LOCAL FACTORS
REGULATION pf BONE METABOLISM by which LOCAL FACTORS: (3)
- PROSTAGLANDINS
- GROWTH FACTORS
- CYTOKINES
REGULATION pf BONE METABOLISM by which LOCAL FACTORS:
PROSTAGLANDINS:
(what are they, what are they produced by, what do they do)
- Small FATTY ACID METABOLITES
- PRODUCED by OSTEOBLASTS
- INCREASE and DECREASE OSTEOCLAST ACTIVITY
- mediate some actions of Growth Factors and responses to Mechanical Loading
what are PROSTAGLANDINS PRODUCED BY
OSTEOBLASTS
REGULATION pf BONE METABOLISM by which LOCAL FACTORS
GROWTH FACTORS:
(produced by, examples, what can they do)
- PRODUCED by OSTEOBLASTS,
DEPOSITED in BONE MATRIX (often in large amounts) - Transforming growth factor ß, bone morphogenetic
proteins, - insulin-like growth factors I &II,, fibroblast growth factors
- platelet-derived growth factor
- may mediate some hormone actions
REGULATION pf BONE METABOLISM by which LOCAL FACTORS
CYTOKINES
(produced by, what do they do, examples)
- normal PRODUCTS of IMMUNE CELLS and BONE CELLS
- mainly INCREASE OSTEOCLAST RECRUITMENT & ACTIVITY
therefore BONE LOSS - eg interleukins-1,2,3,4,6,10,11,13; tumour necrosis
factor TNF, RANK ligand; colony-stimulating factors
*some interleukins may MEDIATE PTH, 1,25(OH)2-VITAMIN D3 ACTIONS
*SEX STEROIDS may INHIBIT PRODUCTION of some INTERLEUKINS like IL6
what is RHEUMATOID ARTHIRITIS
INFLAMMATORY JOINT DISEASE - BONE LOSS DUE TO INFLAMMATION
- Features: joint swelling, cartilage and bone erosions
-Both local and systemic bone loss
- Affects about 1% of the population
- Women are affected three times as frequently as men
- Onset is usually in the patients’ thirties and forties
TYPE 1 COLLAGEN is secreted as an … and undergoes..
IMMATURE PROTEIN
undergoes CLEAVAGE of TELOPEPTIDES outside the cell
