Formation and Resorption are continuous and homeostasis is maintained by balancing them
Normal balance results from osteoblasts laying down new mineral to fill in ditches created by osteoclasts
Imbalance can result from an increase or decrease in either of these processes
Net bone loss = Osteoporosis (trabeculae are perforated by excessive resorption)
Post menopausal
Þ Ý resorption
Senile
Þ ß formation
Net bone growth can result from
Ý bone formation or ß bone resorption
Constant turnover has advantages:
Repairs the tiny fractures that continually occur as a result of daily living (walking, running etc.)
Allows for growth by remodeling bone into new shapes (ie. maintenance of the growing metaphysis)
Adapt to mechanical loads by shaping bone to provide best support.
provides a mechanism for Ion Homeostasis
Bone Adapts to Mechanical Loads
by regulating the activity/number of blast/clast to modify bone mass and architecture
Use affects bone mass
Disuse causes bone loss: Disuse Osteoporosis results from immobilization, bed rest, or space flight
Increased load (i.e. Exercise) causes resorptive surface to become formative thus increasing bone mass.
osteocyte may be the cell that transduces mechanoreception
Their distribution is ideally suited for this purpose
They possess mechanisms which seem to function in transmitting signals throughout the bone
Gap junction
allow synsytial communication
Signaling cascades (i.e. Ca2+
Þ IP3) can result in the production of cytokines and growth Factors
Proposed Mechanism for Mechanoreception:
Stretch Channels
: ion channels that open in response to stress on cell membrane (i.e. Ca2+)
Extracellular Matrix receptors
: stress
Þ transduction to signal pathways.
Integrins of the Focal Adhesion Complex are candidates for this mechanism
Electric Current
: mechanical forces can induce electrical current in bone (Piezo electricity = charges of electricity induced in a crystalline substance by the application of pressure).
Applying electrical current to bone is used clinically to stimulate bone growth.
Neuroregulation
: Bone is highly innervated, thus nerves might detect stresses and respond by secreting factors that alter resorption or formation (ie. VIP stimulates resorption by mimicking PTH).
Ion Homeostasis
Bone mineral is basically Hydroxyapatite (Ca2+)10 (PO43-)6 (OH-)2
Ca2+ can be replaced by K+, Mg+, Sr2+, Na+, or Pb2+
PO43- can be replaced by CO3-
OH- can be replaced by F-
bone can buffer extracellular levels of many ions by either releasing or sequestering them.
Phosphorus:
Blood phosphate level maintained by hormonal regulation of bone formation/resorption, intestinal absorption/secretion, and renal filtration/reabsorption
pH:
Acid loads induce resorption causing release of CO32-, PO43- and OH- which buffer the acid
Therefore, chronic acid loads like those induced in Distal Tubular Renal Acidosis
Þ bone loss
Calcium:
Blood calcium level is also maintained by hormonal effects on bone, intestine, and kidney
Hormone secretion regulated by extracellular calcium levels which are detected by the calcium receptor (similar to the serpentine G-protein family of peptide hormone receptors)
Importance of the calcium receptor is confirmed by mutation in Familial Hypocalciuric Hypercalcemia
Endocrine hormones alter bone turnover by affecting bone formation and/or resorption
Primary Effects
Peptide Hormones: have Cell membrane receptors that indirectly regulate gene expression
PTH
(Parathyroid Hormone): Stimulates resorption.
in osteoblasts it activates both cAMP (Þ CREB) and PLC pathways.
absence or mutation of this receptor Þ Pseudohypothyroidism
Calcitonin
: Inhibits resorption.
In osteoclasts it activates both cAMP (Þ CREB) and PLC pathways.
These are the same pathways that are activated by PTH in osteoblasts.
Growth Hormone
: Stimulates formation by inducing production of IGF-1 (Insulin-like Growth Factor-1) in osteoblasts.
Steroid Hormones
: have intracellular receptors that directly regulate gene expression
Estrogen
: inhibits resorption
Vit D3
: stimulates resorption (via paracrine signal from osteo-blasts to –clast)
receptors for the active metabolite 1,25-dihydroxy vitaminD3 was the first gene linked to osteoporosis (may only be true in women)
Glucocorticoids
: inhibit formation
Secondary effects:
Often can be opposite to primary effect
PTH decreases bone mass, however, PTH in low intermittent levels can Ý bone mass (probably via induction of IGF-1 by osteoblasts)
Tissue Specificity of hormones:
Only a limited number of cell types have receptors for some hormones: calcitonin/osteoclasts
Different cell types may respond differently to the same hormone:
Example: Estrogen Receptors are ubiquitous
However, estrogen has different effects on the same gene in different cells
Some estrogen analogues are agonist in some tissues but are antagonist or inactive in others.
Clinical significance: Tamoxifen blocks estrogen in uterus and breast but not bone = desirable for therapy
Raloxifene: similar = SERM
Diversity of response is generated by receptors being linked to different complementary proteins.