Lecture 34 Flashcards
1
Q
Bone remodeling ends when bone growth is completed.
A
FALSE - it is a continuous process through life and is used to establish the optimum bone strenght by repairing microscopic damage (microcracking) and to maintain calcium homeostasis.
2
Q
What are the four steps of bone remodeling?
A
- Activation
- Resorption
- Reversal
- Formation
3
Q
What occurs during the activation stage of bone remodeling?
A
- Osteoclast precursors recruited to haversian canal and differentiate into osteoclasts
- Osteoclasts line the bone lamella facing the canal and work from inner lamella toward the outer lamella
4
Q
What are the classifications of the lamella?
A
- Inner lamella (innermost layer)
- Consecutive lamella (middle layer)
- Outer lamella (outermost layer)
- Interstitial lamellae (residuals of the remodeling osteon)
5
Q
What occurs during the resorption step of bone remodeling?
A
- Additional osteoclast precursors recruited as resorption progresses slighlty beyond the boundary of the original osteon
- When osteoclasts stop removing bone, osteoblasts appear
6
Q
What occurs during the reversal step of bone remodeling?
A
- Osteoblasts reverse resorption by organizing a layer inside cavity and secrete osteoid.
- Cement line indicates boundary of newly organized lamella
- Bone lamella continue to be deposited toward the center of the osteon
7
Q
What occurs during the formation step of bone remodeling?
A
Osteoblasts continue laying down bone and become trapped within mineralized bone matrix, becoming osteocytes that form the new osteon/haversian system
8
Q
What is osteoporosis?
A
More bone is reabsorbed than is subsequently produced
9
Q
What is released from the osteoclast as it begins to resorp areas affected by microdamage?
A
Liberated matrix bound growth factors
10
Q
What is the function of the liberated matrix bound growth factors from osteoclasts?
A
Proliferation of osteoprogenitor cells
11
Q
What proteins are used to mature and proliferate osteoprogenitor cells into active osteoblasts?
A
- Runx2
- Wnt
- Bone morphogenic protein (BMP)
12
Q
What proteins are peripheral on active osteoblasts that are important for binding Wnt?
A
LDL receptor-related proteins 5 & 6 (LRP5/6)
13
Q
What do surface osteoblasts help to create?
A
Osteclast precursor, the mediators of osteoclastogenesis.
14
Q
What is the first stage of the osteoclast?
A
Monocyte, derived from bone marrow
15
Q
What causes a monocyte to become a macrophage in osteoclastogenesis?
A
Macrophage colony-stimulating factor (M-CSF) ligand from osteoblast binds to the M-CSF receptor on the monocyte, which induces the espression of RANK.
16
Q
What causes the macrophage to become an osteoclast precursor in osteoclastogenesis?
A
RANKL on the osteoblast binds to RANK and commits the macrophage to osteoclastogenesis, where upon it becomes a multinucleated osteoclast precursor.
17
Q
How do osteoblasts know to release M-CSF and express RANKL?
A
PTH binds to the PTH receptor on the osteoblast.
18
Q
How does the osteoblast regulate the amount of osteoclast differentiation?
A
By producing osteoprotegerin which inhibits the osteoclastogenesis by binding to the RANKL on the osteoblast.
19
Q
What is the cell called once the osteoclast precursor detaches from the osteoblast?
A
Resting (nonfunctional) osteoclast
20
Q
How does the resting osteoclast become functional?
A
The sealing zone appears by the use of AvB3 integrin and the ruffled border appears.
21
Q
Other than PTH, what other protein stimulates osteoblasts for osteoclastogenesis?
A
Vitamin D
22
Q
What disorder impairs the balance of osteoprotegerin and RANKL in osteoclastogenesis?
A
Hypercortisolism
23
Q
How does abnormal function of osteoclasts affect physiologic conditions?
A
- Absent bone remodeling
- Osteopetrosis
24
Q
What is osteopetrosis?
A
“stone-like bone”; a group of hereditary diseases; the bone is abnormally brittle and the marrow canal is not developed
25
What is the structure of the sealing zone?
Around the circumference of the ruffled border actin filaments accumulate to form a sealing zone along with AvB3 integrin and osteopontin
26
What is the purpose of a chloride channel in the ruffled border?
Prevents excessive rise of intracellular pH
27
What is the purpose of the bicarbonate-chloride exchanger just above the sealing zone?
To maintain cytoplasmic electroneutrality within the osteoclast.
28
What is the purpose of the H+-ATPase pump in the ruffled border?
In order to release the generated protons from the CO2 and H20 reaction in the osteoclast (creates protons and bicarbonate).
29
Why would the osteoclast want to release protons?
To create an acidic environment in Howship's lacuna/subosteoclastic compartment for solubilizing mineralized bone
30
What pH is required for solubilizing mineralized bone?
Approximately 4.5
31
What is the purpose of the osteoclast synthesizing cathepsin K?
To release it into Howship's lacuna to degrade the exposed organic matrix following solubilization of materils by acidification
32
What materials can be found in the exposed organic matrix that is taken up by cathepsin K?
Collagen and noncollagenous proteins
33
What are the two major cuases of osteopetrosis:
- Mutation in M-CSF gene (abnormal osteoclast differentiation)
- Deficiency in carbonic anhydrase II (marble bone disease)
34
Wha are the symptoms of marble bone disease?
- Exophthalmos
- Deafness
- Facial paralysis
- Speech impediment
34
What is exophthalmos?
Bulging of eyes
34
What structural changes occur with marble bone disease?
Thickened cortex and relatively small size of the medullary canal
35
Cancer metastasis to bone is a serious complication for patients with what diseases?
- 70% of patients with advanced cancer of the prostate
- 70% of patients with advanced cancer of the breast
- 15-30% of patients with lung cancer
36
What are the two types of bone metastases?
- Osteolytic
- Osteoblastic
37
What makes a bone metastasis osteolytic?
Excessive osteoclast numbers or activity
38
What makes a bone metastasis osteoblastic?
Excessive osteoblast activation and bone deposition
39
What are the factors that account for frequent bone metastasis?
- Tumor cells express specific humoral factors that stimulate osteoclast formation
- Tumor cells arrive in bone marrow at a high rate because it is rich in blood flow
- Tumor cells stimulate neovascularization and further tumor growth, as bone is a repository for many growth factors which are liberated locally by osteolysis
40
What is the process of osteolytic bone disease?
1. Metastatic tumor cells release factors that stimulate osteoclastic recruitment and differentiation
2. Osteoclasts begin to break down bone
3. Bone resorption results in the release of growth factors that stimulate tumor-cell growth
4. Tumor proliferates and produces substances that increase osteoclast-mediated bone resorption
41
What is the process of osteoblastic bone disease?
1. Metastatic tumor cells release growth factors to stimulate osteoclast activity
2. Tumor cells also secrete growth factor that stimulate osteoblast activity
3. Excessive bone formation around tumor-cell deposits (osteosclerosis)
4. Osteoclastic activity releases growth factors that stimulate tumor-cell growth.
5. Osteoblastic activation releases unidentified osteoblastic growth factors to stimulate tumor-cell growth
42
What is osteosclerosis?
Excessive new bone formation
43
What is Parathyroid Hormone-related Peptide (PTHrP)?
Protein encoded by a gene entirely distinct from PTH, can cause hypercalcemia in certain malignancies.
44
Where is PTHrP synthesized?
Unlike PTH (only synthesized in parathyroid gland), PTHrP is made in a variety of both normal and malignant tissues.
45
How does PTHrP function?
PTHrP mimics the action of PTH on kidney and bone (PTH1R receptor recognizes PTHrP with an affinity similar to PTH)
46
What is multiple myeloma?
Clonal proliferation of neoplastic plasma cells or their precursors committed to plasmacytic differentiation
47
What do multiple myeloma cells produce?
Pro-osteoclastogenic cytokines (IL-3, macrophage inflammation protein-1 alpha and beta, & tumor necrosis factor alpha (TNFa))
48
Where does the multiple myeloma form?
Often involves random foci of plasma cell proliferation on the bone, which might be extramedullary (outside of bone marrow) or solitary (only one tumor)
49
Multiple myeloma patients can have both osteolytic and osteoblastic bone metastases.
FALSE - they will only have lytic bone lesions
50
Other than pro-osteoclastogenic cytokines, what else do myeloma cells produce?
- Dickkopf-1 (DKK1)
- RANK Ligand
51
What is the function of Dickkopf-1 (DKK1)?
Inhibitor of beta-catenin-depenent Wnt signaling, which inhibits osteoblasts and new bone formation
52
Osteoporosis is the most common abnormality of bone
TRUE
53
What aspects of the bone is lost with osteoporosis?
The organic bone matrix (osteoid) and minerals, which leads to decreased bone mass, density, and thickness of the cortical and trabecular bones
54
Osteoporosis is more common in men than woman.
FALSE - Men have greater bone mass, meaning it takes longer to develop osteoporosis
55
What are the odds of osteoporosis-related fractures?
- 50% in women over 65
- 20% in men over 65
56
What are the types of primary osteoporosis?
- Idiopathic in children and young adults
- Postmenopausal type (most common)
- Senile type in men and women
57
What can cause secondary osteoporosis?
- Underlying disease (hypercortisolism and renal disease)
- Drugs (heparin)
- Hypogonadism (hypopituitarism)
- Malnutrition (anorexia nervosa)
- Space travel (lack of gravity)
58
Secondary osteoporosis is the most common form of osteoporosis.
FALSE - primary is responsible for 80% of cases in women and 60% in men
59
Prevention for osteoporosis
- Calcium and vitamin D supplements
- Stop smoking (inhibits osteoblast activity)
- Weight bearing exercise/vigorous walking (not swimming or anything that reduces bone stress)
60
Treatments for osteoporosis
- Bisphosphonates (inhibit bone resorption)
- Antibodies against RANKL (inhibit osteoclastogenesis)
- Calcitonin, estrogen supplemntation (inhibit osteoclasts)
61
Effect of estrogen on osteoclasts and osteoblasts
Inhibits production and action of osteoclasts and enhances osteoblasts
62
What is hypercortisolism?
Glucocorticoids increse production of RANKL and decrese production of osteoprotegerin by osteoblasts, which increases osteoclastogenesis and promotes bone loss
63
How does nephropathy lead to osteoporosis?
- Failure of reabsorption of calcium results in hypocalcemia
- Low calcium leads to secondary hyperparathyroidism which causes differentiation and multiplication of osteoclasts
- Calcium released by osteoclasts are still excreted by dysfunctional nephrons, and it repeats until osteoporosis forms.
64
How does end-stage renal disease lead to osteoporosis?
- Kidneys are not able to excrete phosphate and do not convert enough vitamin D to its active form
- Insoluble calcium phosphate forms and removes calcium from circulation, which decreases absorbed dietery calcium
- The resulting hypocalcemia leads to secondary hyperparathyroidism which causes differentiation and multiplication of osteoclasts.
- Dietary calcium still cannot be absorbed due to high levels of phosphate, leading to osteoporosis
65
Where is calcium mainly absorbed?
Transports along the nephron and filtered calcium is absorbed at each segment
66
Where is phosphate mainly absorbed?
It is absorbed primarily by the proximal tubule.
67
What causes nutritional secondary hyperparathyroidism?
- inadequate vitamin D3
- Excessive phosphorous
68
Effects of nutritional secondary hyperparathyroidism
- Generalized skeletal demineralization
- In more advanced stages, there are maxillary anomalies due to deposition of osteoid and proliferation of fibrous connective tissue, and distortion of limbs by palpable fractures without mineralized calluses.
69
What is the bone replaced by in osteoclastic resorption?
Proliferated immature fibrous connective tissue and neocapillaries
70
What degenerative bone disorders are characterized by a defect in the mineralization of the bone matrix (osteoid)?
Rickets and osteomalacia
71
What are the most common causes of rickets and osteomalacia?
- Deficiency of vitamin D
- Activation to calcitriol
- Receptor for calcitriol
72
What is rickets?
Observed in children and produces skeletal deformities
73
What is hereditary vitamin D-resistant rickets?
A rare form of rickets because of a mutation of calcitriol receptor
74
What is osteomalacia?
Observed in adults and caused by poor mineralization of the bone matrix
75
Mechanism of the antirachitic effect of 1, 25-dihydroxy vitamin D (Calcitriol)
Increases calcium and phosphate absorption from gut -> increased plasma concentration -> kidneys ensuring balance between ions which get deposited in bone and increase bone mineralization.
76
Effects of parathyroid adenoma on bone:
- Osteoporosis
- Osteitis fibrosa cystica
- Fractures
77
Effects of parathyroid adenoma on kidneys:
- Nephrolithialsis (kidney stones)
- Nephrocalcinosis (calcium salt buildup)
- Polyuria (higher urine volume)
78
Effects of parathyroid adenoma on brain:
- Depression
- Seizures
79
Effects of parathyroid adenoma on GI tract:
- Peptic ulcers
- Gallstones
- Acute pancreatitis
80
Name two molecular defects in sporadic adenomas:
- Cyclin D1 inversion (segment of a chromosome is reversed end-to-end; position next to PTH gene)
- MEN1 mutation
81
Causes of hypoparathyroidism
- Developmental
- Genetic
- Autoimmune
- Iatrogenic
- Idiopathic
82
How is hypoparathyroidism caused developmentally?
DiGeorge Syndrome; parathyroid glands (and thymus) absent
83
How is hypoparathyroidism caused genetically?
Activating mutations of CaSR; chief cells assume serum Ca is elevated when it is not
84
How is hypoparathyroidism caused via autoimmune method
Targeting CaSR, constantly activating it
85
How is hypoparathyroidism caused iatrogenically?
Accidental removal of normal parathyroid glands during thyroid surgery (thyroidectomy)
86
How is hypoparathyroidism caused idiopathically?
Results in failure of tissues to respond to parathyroid hormone
87
What is hypocalcemic tetany?
Resultant hypocaclemia opens up sodium channels in excitable cell membrains -> depolarization and firing of action potentia, causing spasms
