Human Physiology, 14th edition (2016)

Regulation of Metabolism 691

maintained by hormonal control of the intestinal absorption and

urinary excretion of these ions. These hormonal control mecha-

nisms are very effective in maintaining the plasma calcium and

phosphate concentrations within narrow limits. Plasma calcium,

for example, is normally maintained at about 2.5 millimolar, or

5 milliequivalents per liter (a milliequivalent equals a millimole

multiplied by the valence of the ion; in this case, 3 2).

The maintenance of normal plasma calcium concentra-

tions is important because of the wide variety of effects that

calcium has in the body. Calcium is needed for blood clot-

ting, for example, and for a variety of cell signaling functions.

These include the role of calcium as a second messenger of

hormone action (chapter 11), as a signal for neurotransmitter

release from axons in response to action potentials (chapter 7),

and as the stimulus for muscle contraction in response to elec-

trical excitation (chapter 12).

Bone resorption begins when the osteoclast attaches to the

bone matrix and forms a “ruffled membrane” (see fig. 19.18 b ). The

bone matrix contains both an inorganic component (the calcium

phosphate crystals) and an organic component (collagen and other

proteins), and so the osteoclast must secrete products that both dis-

solve calcium phosphate and digest the proteins of the bone matrix.

The dissolution of calcium phosphate is accomplished by transport

of H^1 by a H^1 -ATPase pump in the ruffled membrane, thereby

acidifying the bone matrix (to a pH of about 4.5) immediately

adjacent to the osteoclast. A channel for Cl^2 allows Cl^2 to follow

the H^1 , preserving electrical neutrality. The H^1 is derived from

carbonic acid, and the Cl^2 is obtained by an active transport Cl^2 /

HCO^23 pump on the opposite side of the osteoclast ( fig. 19.18 b ).

The protein component of the bone matrix is digested by

enzymes, primarily one called cathepsin K, released by the

osteoclasts. The osteoclast can then move to another site and

begin the resorption process again, or be eliminated. Interest-

ingly, there is evidence that estrogen, sometimes given to treat

osteoporosis in post-menopausal women, works in part by

stimulating the apoptosis (cell suicide) of osteoclasts.

The formation and resorption of bone occur constantly at

rates determined by the relative activity of osteoblasts and osteo-

clasts. Body growth during the first two decades of life occurs

because bone formation proceeds at a faster rate than bone

resorption. The constant activity of osteoblasts and osteoclasts

allows bone to be remodeled throughout life. The position of the

teeth, for example, can be changed by orthodontic appliances

(braces), which cause bone resorption on the pressure-bearing

side and bone formation on the opposite side of the alveolar

sockets. Peak bone mass occurs when people are in their 30s,

and subsequently begins to decline. By the age of 50 or 60, the

rate of bone resorption often exceeds the rate of bone deposition.

Despite the changing rates of bone formation and resorp-

tion, the plasma concentrations of calcium and phosphate are

Figure 19.18 The resorption of bone by osteoclasts. ( a ) A photomicrograph showing osteoclasts and bone matrix.

( b ) Figure depicting the mechanism of bone resorption. (1) The bone is first demineralized by the dissolution of CaPO 4 from the

matrix due to acid secretion by the osteoclast. (2) After that, the organic component of the matrix (mainly collagen) is digested by the

secretion of enzyme molecules (an enzyme called cathepsin K) from the osteoclast.

Osteoclast

Bone

resorption

HCO 3 – HCO 3 –

H 2 CO 3

H+

H+

(b) H+–ATPase pump

pH 4.5

dissolves

CaPO 4

Enzyme

digests

collagen

proteins

Enzyme Ruffled membrane

Vesicle containing

digestive enzyme

Cl–

Cl– Cl–

2

1

Osteoclast

Osteoblasts Bone matrix

(a)

FITNESS APPLICATION

Microgravity (the weightlessness of space) affects most

body systems, including the skeletal system. Bone depo-

sition by osteoblasts balances bone resorption by osteo-

clasts in healthy people on Earth, but in astronauts in

space the balance is shifted in favor of bone resorption by

osteoclasts. This causes an osteoporosis-like loss of bone

mass as calcium phosphate is dissolved, producing weaker

bones that are subject to fracture. Bone loss begins after

only a few days, and can reach as much as 20% when

astronauts are in space for a few months. The shift of cal-

cium from bones to blood also increases the risk of kidney

stones. Exercise and good nutrition help, but the loss of

bone (and muscle) mass remains a problem for extended

human stays in space.