5

20/3/2013

Salim Khresha #5

Slides

Calcium Homeostasis, Parathyroid

Functions.

☒Slides

☐Sheet

☐Handout ☐Lab

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/ J , .:,Y· /~<"".-.. ·--·, ... / / ./ ' ,_. . '--: / (i_. . -- ! :::::>--.._ '

y' ~ / ~ .' / .:::::::- ,~_;,~_ i ,~_r--' ~ /"/ ~/r,. \ · :1.

I <y~/jv v PAR-AT~lYROIDS D Ft!UR smal/qlands composed oLcordsofCells

./ '-"'_) __ :_~

/

l/ ~-·

~

Thyroid gland---~~-7- @. -~~trmllil;~~

. ~t>···· ·.\:: "-·~~ ~ \,.._ "'-) lJ~•...,:I.:D.J

Parathyroid glands (located on postRrior side of the thyroid gland)

·1--- Chief cell

,,,.'b'/ Oxyphil cell

.G:..'\'7 Red blood cell

Figure 79-10 The four parathyroid glands lie immediately behind the thyroid gland. Almost all of the parathyroid hormone (PlH) is synthesized and secreted by the chief cells. The function of the

_____________ Q~y_phiLcellsJ.s_uncec.taln,_buLthe-Y--maY--b-€-.mG.di~e4-or--d0f:JieteEl---- ---- ·--­chief cells that no longer secrete PTH.

.... '"

~

1-The parathyroid glands develop at 5-14 vveeks of gestation.

2- P1__,H is a single chain protein (9600 molecular weight) that contains 84 an1ino acids.

1__,he biologic activity of the hormone rer:j~.Jc;;:;

·within a.a.l-34. 3- PTH interacts with receptors on the surface

of the target cells increasing the formaJiorJ of cAMP, IP & diacylglycerol.

4- PTH is free in plasma with half life 25 n.1. 5- PTH is essential for life, without it Ca+·+·

falls in plasma neuron1uscular excitability ·t,~ tetany & death occurs.

6- The dominant regulator of PTH secretion is the plasma Ca++ level.

7- Ca++ also regulates the size & the number ~)f parathyroid cells.

8- Hypomagnesemia stimulates PTH secretion_ such as Ca++ but less potent.

9- Arise in plasma phos_P-hate_c.onGen-t-ratioiT--~---

----------imtirecflyCaus~ tran_sient t in .. PTH -seereti oiL

10- 1,25 (OH)2 -D directly redues PTH secretion.

+ Urinary excretion of phosphate

-t Plasma calcium

t Plasma PTH

+Plasma 1 ,25-(0Hh 03

-f Urinary excretion of calcium

t Release of calciun1 into plasma

·------,....;-------'-------,

t Plasma calcium

·~

..

G,Q.l:\¥i¥jEffects on)araJfiyroun1ormone _____________ --------------------

,~~;:;.;.~';._..:._:..;_. __ ; '"-·- · (PTH) on calcium and phosphate

metabolism; -

r:

II

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; ~ . . I I I ~- :! ··. -~~ ... 'I

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. · :··,, ;;·:~

. I

PHi

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:··,:,-:~:L:;:;. ·.:., _;-

I Calclurn Plaama

.. -~~-:~~. { ~-;.:?r;·\L . ··-... \. ~· . . ·~ .. -~:~· .: . . ; ; ~ ' .... i

\ l

I I l

I

Kidney

;

~ ... -:-:·:, • ol ... ~- :~.; ~-;

FIGURE 38-7 Overview of parathyroid hormone (PTH) actions. PTH acts directly on bone and \.:· ::: . . -~-G

kidney to increase calcmm Influx Into plasma. By stimulating 1,25-(0Hh-D synthe&ls •. PrH.~~~:i'g.""l~}., rectly also lncreaees calcium absorption from the gut. Thus plasma calcium levellncreases~:lf!-~)~~1~;· contrast, PTH Inhibits renal tubular resorption of phosphate, theroby increasing urinary phos·.:h~'C: phate excretion. This effect quantitatively offsets entry of phosphate from bone and gut. Ther~~:.X/; fore plasma phosphate level decreases. . · :.:.:_· .. ; .

. _;: :' -~~ :_ .. ~:· ~ ... ,. . ·. ~

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U i'-J DERACTIVITY of PARATHYROI !DS I . .

. ····f""'''

Atrophy or .riZmoval of .Para thyroid tissue causes a fall' in .BLOOD CALCIUM .I<Z~~! and incrrzasrzd excitability. .of Neuromuscular tissue_. · ·-Th)~ leads~ to sevir~ -·n·: ;::::--

.. I;.·,:.·,. convulsive q1;sorder -TETANY;. :>·.- :.:-:·· I l .t~ • ~': :'' :!·l'" :;: : ~--~~:"( :·~:. :-··

PARATHYROID.! GLANDS I •

- I , • ' ~ ~• . __ · ~. : • ;· · ln.3.qequa te · ;: .;;

Production of PTH .............. ..... ......

(/sua/ Manif'est.crtions:- ·. 1 ••

TWITCHINGS, NERVOUSNESS, OCCASIONAL SPASM5 OF FACIAL AND LIMB MUSCLES.

80NE~ Reduced

., , mo6i/izBt/on '',or Ca and P ·&.'/f Increased

.. ·'_,fs.mount.s o;6 b~ndPt'n

:,!.''! :11·1 I: .•

. ' ·'·. ~ .,_ . i. --•. ·: .

:: -·~-!.t~-)~~:;~

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_.:·. :::"'-<.:: .. · . ·; .. :; !

~·~;w;:·:?Et : .. ,:_., --! ... I

.. I .•. '·~',,.'I. . . ' , bon.;zs \ I 11 ... - ·~ '. \ \ ~,:. I \ f, 1 \at •,!, .. : 1 I

t \ TETANY · :!~:;/:~·.:.· . • • ........ '.) ·'. '1\ll :

Vdamtn D matabo!tfaE , . . ~--sz· d..... \ . -u,;I.H '}·~·· · not canvarttZd to v/mtr;tst~a 'J. 1 ·:: ii~:t'".l~;<·-

/•25 JJHCC tubular ' 1 ·• , (~•=:-·t·;.y_:· • 1 rrzabso.r: tion ofCa I ·._- -~--~~~!~ 1~.,-\·t·

1 .-.nd" 'P !')' \ 1 /r conc.·~ntr""t-'on ol --.• · : dacr,z.,sed / \1 \ 1 C6' in .6/ood 1'4//s:-; •. ('.o;!_( I phosphatu. I r \ \ balow 6mg/IOOml (1!: : 1 • . tncre.ase . . /. s '·'' r. 1 1

rzxc!'ac,on . · · . ' . ' . P <Y. mo! ::·:·, ... I :

I 1n urmary ' \ · , .. 1 ;.()-:1;·•1(·!··,·: C 1 ... · · 1 • r1· · ,r · :

\ 1 al \ \ · · · :·. :y~:~t~::.rc~ i , j ' ' · · · ·;, ;~.:l;;-:•::1 . .: I

' \ \ : .. .-- : ~ i~!-~;; ~~;,~::.· :: .,· \ \ \ .·. . .• ,.,,,l.'"i':i·?.

" ' , ...... ·.··· ·:.·,~·-'\·: .... ~.\.:! ::t... ' \ . ., ... . . ......... : ·-...~ -Gill , ', Fall in Concentration~.C?~N.r-i

' .,,,,~ ' .. • 0 d Cal I ·-'·"\' • . ,,, . · . ·· ....... ', ... ~ ron1ze c1um -:,: •. : •. :~.:L

, Dtmtnlshrzd .... ....,..... r.R · · 1 .. •-: r.·(-,':~·-.-obsorpt/on of "' .. _ - # L ~ IS(Z ;n P._tcrsma .. 1. ~ ':~:'·':

\. • 0 • ... .. .... .. ,. "".. • .'.'.~'::.: '''l'llllh, a'trztary Ca - ~---------- phospha~e ,-.,~:;·::~ ~ J' . .. ____ -.- ----0~. --:---.. ·;;_/(;,;;:t:--

---{N-O.t-'--th-12-LL]Jt..C!_L_S..e_Lf2._ja__tt._'a_;_siu.P br2twrzen plasma ca!ct'um and /17organt'p ph~spha_~o/.(:· . ·· . . -. .::.~.:·J~im-:· --·- -·

•. . -... ,,) .. 1.1•'

Symptoms arrz re!J~vad hy /n;'ection of Calcium, large. doses of a Vit.D com-;:~~';'{.' pound and Pardthornu:Jne. · - ·-,:-:::::~l~·:{f~:f.:-;·. ·

- ---· ~;.-·

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-·::' ·.~!{-.::.1-\..lV." _.._

·--- ·~-" . ._ .• :x .... ._,_, __ ,~-:-

i 0

OVERACTIVITY of PARATHYROIDS . '.; _, . i : .. ' 0 0 • ,

Ovaractiv-ity of the Parathvroids (due often to tu;nour) l<Zacls to riscz BLOOD CALCIUM levczl and 12ventual1y to OSTEITIS F'IBRQSA CYSTJCA.

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.·1 .I •. . ..

:.I ''. l . . i:;: '., "I• :;;_ ·._.

i ' I :' ; , ,. . '·: :- ;· . i PARATh'YROID; .,· .. ~ . :: ,_. · !':,i:l. .. :!,: .• ·.'·.:-

GLANDS • , I I. .. _ _.:_( ,-_~-

·; '-\_()·_::·.

:.:;~: 0 ,· ' • ! ;_!-: '· .! ·.,! l" .:,_·;-:- .. \> Ovarproductio~_ ~·" : _:~;_:?:;\': ..

ofPTH ~BONE ,·. ·<·:: I •' 't

' Greatly in~f~t!3srzd :·' ·, -:: ' mo6tli.zat/on of ...

Ca and P

!!! ~ & ~ ~~ 0

:\ ~ Eventual -Sort~n/ng· ,, ' ~-::. and de/brmity or bonfZ_S_-.:-_:··,· ..

.. ,ll·f~i'::·· .... ureatly incrrr.asrzd}

tubfJ_Iar ~ o;absffJ_rpt/on of Ca and (:Ybular.--i.

srzcration ot A t 1 : 25 DHCC • ..... ,)1;;~· \

11~ \Great incraasrz in 1

' 1 , I( absorpt/on o'f ''-. d/rzt,;;ry ('c9 . ..,,,,,,,,,,,, ...... ':;.:,..:::;,:

Grrudloss orP/n

Ur/nrz

11

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~(\ .. .:-.,·. \ \ . . :_·;::::-:·:

-=:;~

0. .. :,.·.

Great increas12. in Concentration · of Ca in Blood 1

(Plasma Ca may IJq oYer · • · 16mq/100ml -..lncrrtasrzd

Vir cosily of P/.;u;ma) D~position _of Calcium in · · ·· Unusu~l Sit~s rz..q •. K_idney.~ ..

S1gns ofToxJclty ....- .. ··. (fiaus~a.~vomiting,/o:;s of<ilpplltit~. etc.)

Thrz incnzas12.d lczvtZ.l of blood calcium eventually I«Zads--to --iz-xccissivcz-lo5-- ___ of CALCIUM .in __ URINF..(in spite of t reabso:·ption) ..:..nd also of WATER since. thcz. salt

-----~--,..::ia51Z--4x.ct=e.tczd..iCUiQiution. POLYURIA .:md THIRST re.sult. . .. ·----------

Excision of th.rz overactive Parathyr~-;-;itis---;;u.~.Doli'sn-es-synC/romrz, _------ --

·l

}.:/:· ., ,.

. /""'" /L/ 1 ~,-

! ·-·- ~------·-·-· .•..•.

- . -_ _. :1/~;:.; :.;_~ ; _ _.~<~~::;~~L-• • ·' I I l,).:~;d~~-~::'i10 :~!·i1k'-: . . . ·. ,. "" \· , .... '·'7·. ·J~vJ:.! : 'I;.,~ \',.I ;t;,,_..J. It( I I'Vf . '-.;·::: ::~~l':\:;:;

. ---------- ------------------------. .-~W-!W P. Q@dfll

Preosteoclasts

, ~ ..l--..l._ Osteoclast ~ ~ --.......... , P..cid secretion

···rH v· . 0 OPGL ~ .. ··.. ·x /Lysosome 1·· 1tam1n (.(!Y:V ~ /./\ \ I {? ~© '/ Ruflle~s~:o:~~~;t ~ ® ,,, , , n ~ "" ~~ 6'!/ , ®''';r,·" :~~....:~=--':<Y ~,:l()J u ... ·""'··-'~:~2

----··-~"·-'--

~ Areaof ·~,.._

(( ~.:-~:e . bone resorption _ ····-~:.'~!:_:-- --··-~-_):J ------- ----:7 - -- '· /'./ ~ ._ .... _.... __ - .. _.. . . ,_ .. -

~::::.,.0 \..-.../(" \. . --:>---- ) -) --'"'' ' ~--, ( -( -tffi}J. ·~ _-_.:_;:·'~~-- ;/""'-~'\ .... .. cs ... _ . ., ... /./~ : -- .. ~-:·' / \ ~· ·--' :

(( "·-~( ~2 osteocvte'' ~~ ~ ~:::.--- ~ •·

Figure 79-5 Bone resc;ptjoti- by osteodasts. Parathyroid hor-­mone (PTH) binds to receptor-s on osteobtasts, causing them to release osteoprotegerin liga:·d (OPGL), v.J:ich binds to receptors on preosteoclast cells. This csuses the c;::\ts to differentiate into mature ·osteocla~ts. The osteoclasts then develop a ruffled bor der and release enzymes from lysosomes, as well as acids that promote bone reso ro ti on. 0 st_~r:_y1 e_:; __ a ce__oste..ob1@-£-ts-t-4ai-Aa-vr·--~-----~­

_______ lJecome encased in bone matrix- during b'Jne tissue. producti<H1; the osteocytes form a systen; of inte~:c:>·;n-:::ctEd cells that spreacl•, . all through the bone.

-~"'--·--;-.:-~-':

~: --:-:

~':.·-.

~::-~vitam'in o ..., '~

Vitamin D, in conjunction with PTH, is the sec­ond major regulatory hormone for Ca2

+ and phos­phate metabolism. The roles of PTH and vitan1in D can be distinguished as follows. The role of PTH is to maintain the plasma Ca2 + concentration. and its actions are coordinated to increase the ionized Co?~· concentr.q.tion toward normal. The role of vitamin l) is to promote mineralization of nev;. bone,· and its actions are coordinated to increase both Ca2

+ and . .

phosphate concentrations in plasma so that these elements can be deposited in new bone mineral.

""':-

o Bone. In bone, 1 ,25-dihydrox-ycholecalciferol acts synergistically with PTH to stimulate osteo-­clast activity and bone resorption. This' action may seem paradoxical, since the overal1 action of 1,25-dihydro:-..ycholecalciferol is to promote bone· mineralization. Ho\vever, mineralized "oldll bone is resorbed to provide n1ore Ca2

i­

anci phosphate to ECF so that "nev/' bone can · be mineralized (bone ren1odeling). ----

.. ----~---

(£,

---.;,..._.._--. -. -. ::-. --- ------·-.-:::-. -~- ~-------------

:·_5··-·.:._.":··=o;~.:>.-:;..":::;;;-...::

- Vitamin D & its Metabolism

1. Vita1nin D, is a n1ajor regulator of calciun1 & phosphate n1etabolisn1.

2. Vitan1in D is a hormone in the sense that it is synthesized in the body, although not by an endocrine gland; after

further processing, it is transported via the circulation to act on target cells.

3. It is a vitamin in the sense that when it cannot be synthesized in sufficient quantities, it must be ingested in

rninin1al amounts for health to be n1aintained.

4. Deficiency of vita1nin D causes faiJure of bone n1ineralization & results in the classic disease of rickets in children & softening of the bones (osteomalacia) in adn!ts.

5. The sterol structure of the synthesized form of vitamin D (D3) differs slightly fr01n the form usually ingested (D2).

6. Vitamins D3 & D2 are essentially prohormones that undergo identical processingthat converts them to molecules with identical qualitative & quantitative actions.

7. Once vitamin D enters the circulation from the skin or the gut, it is concentrated in the liver. There it is hydroxylated to 25-0H-D. this molecule is transpo1ied to the kidney where it undergoes alternative fates.

---- ~-z-4;zs=(OHJ2-=-rr-is-only-172Uth-as poteiifas -1 ~2s-=-coH)2~D-------­&mainly serves to dispose of excess vitamin D.

9. Vitarnin D, 25-0H-D & 1,25-(0H)rD circulate bound to a protein carrier. 1 ,25-(0H)rD has by far the lowest

concentration & the shoriest half-life of the three.

t Plasma calcium

+Plasma PTH

t + Renal 1 a-hydroxylase activity

t + 1 ,25-(0H)2 0 3 formation

t +Plasma

1 ,25-(0H)2 D3

Intestine

t Urinary excretion of phosphate

t Urinary excretion ofcalcium-

I + Plasma phosphate

+Calcium absorption

+ Plasma calciu~~~~=:--~=~ ---~----------- ------------------ --··--- ----·- -- ---------- ------- ------------ -----·-------- ---···

.- ·,_: _:.. -.--

,·

.·:_FIG.URE 36:9·\ '... - .. _ ;. . ... ' : . : ... "'-~~

Effects of 1, 2 5 -dihydroxycholecalcifert.t 1'

[t;25-(0H) 2 0 3 ] on calcium and pho_ phate metabolism. I

'. l I

.;. ~--'

1··

•:'· ...

..

.. · ... . ~~.:: . r)} .:i

Dietary source · Intestine · I J I . .._. -• .. •,II ... ' l\\:-._') • ,. ..... j l_S. •

7 Dahydrochaluterol · Skin; UV light

:; ~ ~ i. ; ~= ~ :: J ;

' . , ·~ r! i ~j :! ·'I

' ~ ! I I . ~ I

J .. : Ill(!. 1 ~~~ 'I ! ·., ' '

,::! . ; :1;:- i· l:i 'I

\_tq-.4y li(raxr.1~~~

Calcium excesa ~

Phosphate exceu L--....t

24,25-(0Hh-D

-------------- -----------

'i:l i !_.

~~ it.!:~ • ~. I;: I ': ;1.: :1.:

.,. .•'!. .\:

: . .1. i; · 1: I ; j 1 ~ ~ I :• ; l '·, , . I'

... ;, .. I '1'\ \ :1 ·,i., t., I 1-•',,: i

'.1:' ~~ -::d:(·t~: i·l:i!:lhiJ!

" ' ' 1·.· \ •.

;J:: ·1;\l:p·:w: .· ~'II . ~ : ~! \··.·.,:.~~

'..'I : .. ';~

·'·· · ... ·: ... :·· ·• ~ i • ~ : I• ··. ,1.,.

:, : ,~ \_ ~-~: ,,

,, ... ,

Kidney · ·

n c:&:4iydr" l{yl9

. ·•. ':: . ;).;i;:~l.~; . ,. ·,.·· :.',:\(t,~~1{ik~~J]; .

.. :' .'::· ::=·;~];i~r.~f~~ .. _:;~.~-- !-~·: ...... ;., . ~ ... .

·;_··: .

..

..--}. Vitamin D deficiency

Calcium deficiency

Phosphoto deficiency

Parathyroid hormone '

1,25-{0H)l-D ·-~

- -... -- --- ·-----;- -·

FIGURE 3B·B Vitamin D metabolism: Whether synthesized In the skin or absorbed !rom the d

vitamin D under~be·s =:s hydroxylation in tho :;var. In t.!:e kidney, it is further hydroxylated i.n 1 position when more biological activity is required or in the 24 position when less blal( activity Is required.

: -----------·

~~~ ~ . :. i~~~~ ~- -:: ·tr

. ·' ... :',.:il.nlN ·: -;·:'!-,·.-~X"~

. __.:_ ___ ,-~----==:;:;:;;.· ... 1·'..:~~ .. .::.---~---~. -----.

-~~.: :~=~~~ :..:__;~-:::~.-~::.-

·w· ·;,.·

·•:.-· ': •. -;T: ;,r · g;·t:!:-;::xt~ , /' ;.: · ::H'.>· ~\~¥~~J~~~!~~r::~, ; · _: -· > .,::;;iJ~{~·~;~i~s.::J#

.. - --- -·-~~-~~-·=-~ -_::: -::_--=~-=---~·=·~ ·~~- ~ -~ ·-~ --·--I

II TABLE 51-2. Vi~ D· metabolism in humans . --··- ·r-. --

' Plasma concentration

1.25-(0I-Ih-DJ 24,25-(0Hh-D:; 25-0H-D3

··-- -- ··-··- -~-. -- ---.

('rJ;.giL)

0.03 2

20

_._ .. ___ ........

Plasma half-life (days)

1 to 3 15 to 40 5 to 20

Estimated production rate (~glday)

1· 1

10

~:j

,;,

'·-

I

.\

·-\

:: f

j, '

I i

,, ·J• .!.i

•;t.

\' \ I

[ t Plasma calcium

+Plasma PTH

·t + Renal 1 a-hydroxylase activity

t + 1 ,25-(0H)2 0 3 formation

Kidneys

(/ t Phosphate \ b . ·, rea sorpt1on · · '

t Urinary excretion of phosphate

t t Plasma

1,25-(0H)2 03

t Urinary excretion of calcium ___.:__

I t Plasma phosphate . . -~'--···~ + Plasma calcium ________ j

-···-'FIGiiR·E· is~9·':) EH<!cts of 1,:25-dihydroxycholecalcifer~~ [ t, :2 5 -( o·H) 2 D 3 ] on calcium ·a~d· ph.< .·· ... . -__ ~-" .• ~.' ~ • ' • •-r:~ ,;_••~

phate metabolism. ·

. ~ '·:'.' ·. -~ ( "'-"'" /

!'! Endoc6ne Modulation

,i.

.•..

. --· . - .. - ..:.. ·-,. ~ ~)

~~?::r ·-· -~··

'' __ , ----~ i:

v t ~ Pancreas Pituitary ' Parathyroids

\. ~:\

-....._ . . - I

'· . .....__)

., I

:- .... : I .I

25(0H)D ____ .,.. MAMM,'.'.Y GLAND

PLACC/fiA

SKIN I

AVIAN SHELL G lAr/0 .:~_::..;:; '1:]~.;-:.::..:. : =~-~ .

.... _.,·~.:.-';'"1.:""·"'-:··.·

1\\INERAL TRANSFER .. ·. -~-~ . :-.. ·•.: •-·· 0 '.

l~testine Kidney Bom~

Mineral Homeostasis

Figur~ 8.41. Function ·and regulation of 1 ,25-(0H)2D. (From ·Hausslkr and McCain, 1977.) ;_: I • --

i·

\2\ . ~ ... ..---....

···-----~-. -·~ ~-···-------·--· ..... •• •••"•"'' -•·•.- -·--···- -·-··---..f.-.-----r·--_,__ ... ___ _ I

'' .. Table 7.5 Caus~s:of deficiency of 1 : 25-dihydro?<ycalciferol ·

·Failure to .. synthesize ch.ole¢alciferol in the skin (this occurs in dar1k-skinned

pe.opfe in a tempeiature. cli_mate) i

'

Dietary deficiency: of cholecalciferol {relatively unimportant)

Failure to hydroxylate cholec;alciferol in the 2? position (this· occurs in chronic liver disease; hepatic-osteodystrophy}

. . ·Rapid metaboli~m,·of cholecalciferol and its· active metabolites {this occurs

. 'when-tiepatic.enzy:mes·are.inquced and is se.en in patients taking anti~onvuls.ants)_ ' . i • ~ ..

Failure to hydrox'rflate .25-cholecalcifernl in the 1 position (this occurs in· • I

patient-s with chro~ic renal failure; renal osteodystrophy) .... .L. ••

-~~~--- ... ~ ............. . ... ,._.

---~·/::

;J;'{-N -.~ _.·· ~- ~; :·

!_

---- :::r.:· ·: w:

i -;

/' '

.'1

1

, - ....

.-., .· ~: J. ~

I

. f·.

... : I

... ··-- I· '· I· I

I

I I -- ) II I

·1 .. -~~q~ired·-£9r ,the- maint~nanc~,_of_normal·· ···,. s:odium, permeability in· ne~ves ::· ·· · ,

2. Involved in triggering the release of acetylcholine fro1n ·nerve endings at the neurornuscular junction · · ·

3. Involved in excitation-contraction coupling in muscle cells ·

4. Serves as an intracellular signal· for some horn1ones

5. Required by son1e enzymes for· normal activity . ,

6. Required for blood cl()tting _to occur· noi·mally - . . ..

7-. R~ql:li~-~c:l for protei11 secretion . -s·. Caris titucnl-of bor1.e _______ _

----~'------~----~L-

~ --- ------ J. _______ _

~ "·--

.::~-~~0.~7~:=~

1r ·

I

·. ·---~·.:-:.,=:.;: .. -._:·.-~··: .. ~.:·;.:..:;:

· ........ · . ; -:::-.

~....._,,

··i:: .. ·.·. \ - ·_;_~-----;_~---·-·_....:_ __ . ~---------·:._ ___ ... ___ . J ··----,--:~-~--·-.,-···- ................ ·-··--·--· .. --- - . . . --

.. ~ r~tJ~. h-1.: Distribution (mmoi/L) of cal~ium in normal · · .. · · \ : human plasma.

· ··"_ --_ oitthsible ropizedJCa2+) Cqmple.xed to HC03-,

) ~itrate, etc · \ Non~iffu$ible (protein-bound)

1.18 0.16

·-~ .· Bopnd to albumin . · 0.92 Bound to globulin 0.24

I , ------~_1 __ _

1.34'

1.16

;; . 'I

::.·

·-·\

il I

I _.,\!

\' I

. \' ·i• . I

: . : ~:\ I . 1:.

J . Total\ plasma calciu·m 2.50.

$lo ni:Z ~i:L..Ca :~c.oh<;:ertra tion, depends_ ().fl .. bl ~o d . pH. 41 ka (o sis f n4rea ses the prole in- bo lf ;~fief decreases .... the \ loni~ed ca+ + concentration,wh.Qr.eas acido.sfs has theopposite eff. ·

ect. \

~--- . . .. ,.

I I

\ -...,--+-\ .. ----·-~-. .. ---- .-_..,.--------·

I

\ \. I :·. -.\ . t . ~ . . . \

.. , · .. I

---!.- --

Acidemia Alkalemia

'l 1 t Ionized [Ca21 + Ionized [Ca21

FIGURE 9-32. Effects of acid-bas<! disturbances on plasma prn­tcln-bindlng o~: ~~+: and_ .th~ ~ lo~d·::.ea:z+··· concentra~on in blood ' 'tt '"'~a., : ..... ~.~ •1 t. "' •l <'!I.J ' •'i"•':"'• 0 0

• •• {f • 0

• •' • • ,. • I • • •

--···---··

-------

--==--

_:...._.....__:----· . ~ ........-.:;::.------------"~

I--

1 L, ,_/ I

. \.._ _____ /

-::::-:..:::

--·

~ ' ~

' ".:.1-

~ s; i:. ,._

~ ""

....

' " ~

--~----------"" {

~ ' ' '

1: '

------~;~_: .. -;-_

~· ~}~~·I• F . ~;:

?r··~"-:D~~:_r-~:$~y;~~:-:~-:::_: ,, ·;., ,,:,,·. Calc1u

. ·'', :: ~; .~~. I ~ :.t::·.:_.: ·.

iij:jfEJ·,~~ll~{~~,;c···· Water. '

· ...... :l:·:. ,·.:

·'. ·==\·:--~f;fy~::7!~·;{:cv:::~~~f.~ :: .. _,,::;

;:.·_',;:':?- :·;r"t ·~s·····

. :· ···:

9

~~~;~'~f}!!l!~~r~~~?:~~~g~~~:0)t1~ltf

···. I . .'.

' ·'

-

i ~ .

I

~;,

·'

----; .

I

'

. -...

,~)

ti I:

~~ ·,i';]i\ .. ·. \' ~ : ' ,, ..

\ ··:·' ., ....

' . .. , .

I :!

'I: I .

I. I I

' i

i ~

I . i 1.1

I

I I

Kidneys

t Phosphate reabsorption

J? t Urinary excretion

of phosphate

t r Plasma phosphate 1-

t Plasma calc~

Para follicular cells t CT secretion

+Plasma CT

+ Urinary excretion of calcium

t

~ --......._.,

Bone ). 1 resorption ------t Calciurn

release

t Plasma calcium

t=ltiliRe:·as:a· ~.....::.. --- r - -- • :,_' -

Effects of calcitonin .(CT) on calcium and· phosphate metabolism .

.. ·. "t'~, "'''•l·

.....

I,

' Inhibition of osteoclast

activity

...

·-----

- -- - -- - - ..

---· ··----------- ··--------- ---·-, • ' J \;.• •• 11··.. ,

· . ~ ·· .EI~vat~d . · '· .. , .. plasma·.ca2+·:. .:

;', ·. ~· ; . , I • .

I c.s~/Tl~tati:nOi catci!Onrn- ·I . secretion

by pa~afollic_ular cells ·t. ..

~

Increased . ·plasma

I calcitonin

-

- . ---- - .. - - . - -- - -- ------ -

t

Decrease~ pl~sma Ca2+

-----

-~

.·: , .·•. !ncr e_ as~d · · · :,_:,l··

. . excretic ', and I

l Cf C.,.;?.{ ' ) ,.<d' I o3- b\' .. : ,:: .

;:· .. · .:.·; kic . 4 . ) . . I

neys ··. · ... ,·. ·1 . I

---

~-~;·, L t)

Fig. 12.26 The principal anions of calciconin and cbc bnC;r:.

thoughc co rc,gulacc ics sccrc:cion.

~

_) i.

' ''--:---~

..._, ..

.. -.------... ................

I 'S,")S!J U~UOJ!.1J1!.1 JO )l!l{J ,")l!li"'\ SJ!l!J

.lUOlUJoq P!oJ,(ljJJ!JJ!d ,10 uo~J-'lJ."l./S .ltp 's.">S!.I wn~.'ll'!.l sv ·u!UOJ!J!'!.1

!llll:·.")lJ()lUJOl!!l!CJJ,\ljJI' .. Il:d l(.Wlj JO UCJ!l·)J).l!> .1tp !llll! liO!ll:.IJU.).1ll<l.)

wn!.1!1!./ •:u1s•: 1d .)tp u.).),,\).")q tl!qsuo!l'!l;).f -Ht.t. ~z·z 1 ·:-t!:l

(~_I OjCJWUI} Ulll!:Jit.!::J CW!il.!jcJ

o·z:

Hl_d JO UO!l E?Jj U <DUO:>

Bun etmJ!:J

I . 'I

' .. : ·,,'\ ~ • .... ~:,. ~':-~; ·''· :' • • • ; :. •• c ' ' , • :. I , , i:. I,'. ! ,.-. •I ~, ·.-' .: •j;,' ."

;' :.-: ·. l/IUOjpp:?8 JO UOI\eJjUD:JUO:J

: . 5U!ll:lln:JJI:)

.--·---

....(:---+-~Bue;

\[~WJON

·. ·r:: ! ;

.. !. •, •! I

\

Calcitonin

1. Calcitonin, a straight-chain peptide of 32 an1ino acjds~ has a n1olecular \Veight of 3400.

2. The biologically active core of the n1olecule probably resides in its central region.

3. Calcitonin is secreted by thyroid parafollicular cells knovvn a~:: nell cells.

4. Calcitonin, (CT), decreases plasma calcium levels by antagonizing the actions of PTH on bone.

5. Calcitonin is also present in nervous tissue, where it n:wy function as a neuro1nodulator.

6. The 1naj or stin1ulus to CT secretion is a rise in plasn1a calciurn concentration.

7. The hypocalcemic action is caused by inhibition both of osteocytic osteolysis & osteoclastic bone resorption particularly when these are stimulated by PTH.

8. However, with respect to phosphate, it has the san1e net effect as PTH; that is, CT decreases plasma phosphate concentration &­increases urinary phosphate excretion slightly.

9. The i1nportant(of CT in hutnans is controversial CT deficiency does not lead to hypercalcen1ia & CT hypersecretion does not produce hypocalcemia. It may be that abnormal CT secretion is easily compensated for by adjustment in PTH & vitamin D

--------------- --1-~---1----------------------- ------------------- ----- ------- ---- -------- -- ---------------- ------ --- --- ----- -- ----------eves. -

10. Is degraded within the liver & kidney, after half.:.life of30-60 minutes.

®

'\· •• ").> • ; J:J

,.

)<idney tubule

""''Y Ph I ' ® I PI ·'7. asp late \ asrna + reab•orptJon t phoGphate

t Calcium ' ra,absorptlon/

? :?;s" ---.-­-0

-~r X

@"' . @

*lrta\ ,,,.~) :;~: ·::~

Intestinal absotpU~rtr

1! Blood

.. H~poco,.lcaemla I @ !\\~:~~~;:~·!·;·~~~-~~:H::::::~

0 Hypocalcaemia ·.· :::

\ '4" . 125-HCC I (j)-~

0 )1~:-:~:-::~:-:.:.:.:-:.:-:-:-:-;-:.:.:.:.;.:.:~.-:.;.:.:.:-:-!-!-!·!:!..·.·:::·.·.-.·:::·.·.·=··:-:::..:.;:!:~::·:-:.:;:;:::::::::::::::::::~:;«0;:;:;:;:;:;:::::;:;:;:;:;:;:;:;:;;;:;.;-: PTH

._, ·~·· . . ; · .. I I .. ~.

,. .·.:

...

. I·:·<·~ >- :

...

,j.

'. .-·. ·.-:~.:...;.-: . .... !·\'il;~H

.": --~-~~ ,·~-t-~~-:-~ ·'. · ...

,; 1. (,

I • • . ~ •

;: .

.. !. ' _I''. :.::. :-

: l'' . .f ···"! - :.j ,-;: ~ : . . ': . . . ;-; ~ :· ....

.:. .'·' , ..

--:<=!·::--, ·- .~ ': ._·.-_. .

·~·-· · ......... . . ·;,-;'': ··:_: .. ~ /-

•' ~·:;·:~.:.:--_:: ." .. •-:. :·

,: .·· ... : :; . ·.:: :~.

·.: ·.' ·• : ~ ... Fig. 12.7 A diagram to illustrate the interactions of parathormone, calcitonin and.vi~ami~ Q1.

d ' d . . ' I. h. • • · · · .. · ...... ___ ___!!D___l!§____B!IV.§tiV~S.__Lfl_C8..C.IUill_tLO_fi]80S1aS.IS. - ··-·- .. -. -· -- --- -·-- - --- --- -- -----.--~~··:·;o-- ------......._ . , ....

....

""!"'•" . . "'I'·· . ,.!{lftt-'-j.::~,..;; . : : .. ·.'··· .. : .. :,·>··,,i.:i.:·,:.~·.-.' ... ··;_:{~i~:;·~;

· : · ... :..-~·1\~.J.r. · ~.~ r· ........,-r· :_~:. ::.:;~_.r;_;~!;,i:_ , · · ~'rl,·· . . ·''·:; '

.. tt'r ~': . . ... 1.1'1'1% I'. 'I ~:. I ,-'_ J. •

. ' ··~~· .. ·\ . . ·:r-

~ .. :im.!--;~ --·- ·-· - ··--""'--·----.-· .L_ __ . --·

. --. . -. . -.. -:~

'-

·.-,.. ! ·.- -'-·------

· vw-:ra ::rr:nrv ~y-rozrw..,~ ~y: JOdflo.l'·! cv:fl Von~ ~v

-s 1 IT / I r7'l Y'--v· ~~· dj 1f CVV/f-"1-(d?r ~ t YV¥J""'~-::f. Yj t' _L. ~ ·-s o-( ~'-0

, -fYY'~~!J'(JOJ -Q)·}-LLd -@) ·u ·f'!/'1 -@ ~-(""' ........ (9"? Yi'lr Q \ij . -

- ,' (yvfl 0VJ -y--vW-S 4j y ~ r r ~ 0 i(d c'()~ <"Q j<_l~ CiJ ·-V?~

fj;w~i?(,<tt(jr-- S·a)r.-vv-r-v; ~ (_p~ c.\;- Cl J pj::~~~n~ ?'"-> d-)-~~ J- -df t ~ f~:-vvv ?1?"!--J' }--.9 ~-tY) ~

...;-J ~3 ~ r r r-z> ~ 0 9 ~o-vv ~~ C) 1-

, Y'"" ~""Jff"'> nr-:J\i. 7:i ~ 0-fO'';Y vo }-·erw r.; p~_:v:~. oo-~'-1--- -f-::..-Gw ~ 11 ocJ 1 :P -...., f.\f d~prrd" r - 0 ~ ·~ (- j,.; v l_!)

1~~~ ~~~ · . Ta~~e' · 21:~2~ Factors tha~r_?tf$ct bone·· fcJ"rmaticin i'and · ...... ::~ ....... ·

1''- ·-~-1:·:.~.~it~}]\!··

rr,· I .

. I . : ...... b ~ . . ····.· .. , ; ·' . : : .:.::·, ·- .... : -c--~'. ... calctum meta oltsm. · .· ~ ; :-.~ .. ·:-

··- --··. . -·- . -·-· .: :'~

.. I -

'

l' I

I

Parathyroid hormone 1 ,2-5-D'i.hydroxych·orecalciferor Calcitonin Glucocorticoids Growth hormone and somatomedins . · Thyroid hormones Estrogens Insulin IGF-J Epidermal growth factor Fibroblast growth factor :Platelet-derived growth factor 'Prostaglandin E2 ·

·Osteoclast activating factor

'

\.._~ .............. 1 c-, .) ~

i ~; ' .

I . .

I ...

I . I ' ; I I

I I

; l

I I

il'

/ I )

r~ i'''

I

(+)

.------ 11 '2 501-120

!Ca++ absorption

1!?04-absorption

Gut

t !Ca++

!PO~-

••<:•·~:"'-\'"':';" ..... •'• -• .~· ~· • ._. .~·•, -· ("'~'I

Kidney

11-alpha

hydroxylase

tea++ reabsorption tP04- reabsorption

~ .....

tCa

(' \

I Ca..._ tPO;j-

I j

ICa++resorplion IPO;j-resorplion

Bone

!PO:;-~ "" r-=·_··-····-

~~ Parathyroids

'------------------------------------ ·-····· -···-· Fig.~ 1-3. Integrated phosphate homcoslnsls. The responses lo morkcd decreases of serum phosphate c:nn<:cn tra.­llons are shown; oppos!lc responses occur to marked lncrc<~scs. ( + = sllmulal!on; - = Inhibition; PT/1 cc parathy-roid hormone.! ·

(26 ) .·f,

I ...!

'

I ---·----- ~:::~:~::~i:~~----·- .. -.:~-.-~.··

""-'~

)

~~{~t·ct :·;~- : ...•... , .; •. ,::i-~~::~r;~~Y·· · :> .• ;,-:c:::;:: "'"""' ... ~- · ... : :_ :.- ~. .. .r.·. . "' ...•

~ .. . . -· . . .

--~, ' -\gT'i"- _- . ~ •.. :v· :"~-rx.<:, ·. ~,''·'"""'q;

/ ~ ---- ---··--------- iii;~~--~(:: H - • H - - ' ;;r:

I ~I • - •

..

.\:

fli.it1~1~~~%i:~l&l~~i~~~;~·~!k11~~~~~~1~-;]~~¥@~iff~~~ti~}~jj .t=·~:;:;;.-,J;~ !)J tl ~.d''t i 1 ~\; g ~ • ~3F~ ~~n &l~ @, ~ • ~~1 t:~:i !~(! ~~- ~ ~B"'~'f{:-:;;:::,.<:'''~;:..-:);/~ff-

~~~JXMl~l1~~~jitl.~~1~;f~~}~l.itfl~}~~~~i~~-~~ --- .. ---· ,-"': .. -. . ... :.·. . ·::-· · .. · .... -.. ~~!.'~---~~; .. ·:-=:.-~ •. : . : • • ... 0 : •

· 1. -F~ctioll-$ as. PC3!t of t4~·:Jh~a.e:·~llular buffer sy~~~m . _-. _:·.-.> .. -. . ·; . _:.·:_-)/:~~--r~:~~~;}?'::~:f:- -_:·,:_

2. Imp9rta~t ~onstituent __ .-Q{~~:=;:'y·~-~ty· of m~i~omoieCules, sucl{:A'$~:·'~D.1icle1c ·adds,

. : .··· .. ··. . : ·, ... _ . ~- .... -~:--·'f'-.~-~~::"~ .... .s .. -:.~-.:.:-·:·. ... · .... · !

pht?sph_9Jjpids, metal?·qg¢~)!\~e~ediatesf andi pho.sphoproteins · ·- __ :,_._:.y~":~;-tt:~~,:~=~;_-,','·~- ., .. ··

3. c~listitU'ellt of bone ;::;::,;Jt,:t·(";, !' .

. :~-~.:::·~··.·~~~:.:./: :·:= ... ··

\

( rSJ \ ~~

-

- - . - ---·-·· ------ ·------ .. ··-·· -.- ---- ' . J ·--~r·

·.~ • · ,· ·~~f I ,• • •. ::• ~

: ~

•· i '· I

,.

I .,

I.

-1. .... --------------··----· ---- -··---·-·--· --·

·t C• ~ 1· ·L 1,· ·t: 1,· <t· ~. 1 c· ~· ~~. ·~· 'G\ ·~· .. ~ f. -~ kZ..f~~: ·[J~ t.c·, vl }:}:

.e f. ~ li\ ~E': C· ~~ r t f.. c_ ~· <t· ct· ·~ \ ·~ <o 1 t: h .[c- ~. G\1 ~ ~ ~ :---:_ c ~ E:

:: 0'1 f,:. b I E:.: I c c. -1 \; L. c_ 'b ~ - (• - <: t>· £· II\ .I b 1~. ["

l(i\ ~ ~ 1: I c- ~ ll ;t ~ f 1\ 'f :t ~ I [• "'.·;· , l :J E:- bl[·l v. .. f - ·~ -:: .E· f:... r-1 ' , lj L- ~~· - c_ ~ 1 '&\ e r--·: ' - \)0 I ' ~ (o - ~ I I' I I I' ' (__

il . loo - ~ ~, I • tl -

' 1: ·'t ' : l :t 1;: ft 'P ~t· t :( .[ ~ t . f ·<t·. 1 • 1:: ~ <r/\ ,l>-1 G\ _ ll t• t 'e ~• ~ ~ ' f' c_ f:... . ~ ·1. }!.'11 E:.: r; ~:~~ •C.· ~~I L I ,-;. .c- ~

- ~ c. r £:.: c. - - e-. [ - f:... ~ _ \ ~· f b ~ - ~ ~ IC.,,I~·l· ~· .:_ :~ ~~~. ·~ C_:_

-1 ~· . l' ~ ~· ~· E:.. . r r r l(i\ { • t: c ~ - 0'1

l_ . ~ '". f. J ~ t.'•~:.-1. t ·t ~~·t .~· ~·:r 1:· ~ L 'r. ·~ < ~·~1_: c c· ~ ·t F:~c..·~c... ~ [ - ~ t b\ f' c· ·v ·<~::. I (1 _: :~ ' G\ ~ ~c. 1~1 ~11~ ~ ~ ~I ~~I~ t l, f'' ' ~ ['

E o.. b ft. I -I~ <.. ~ • - (_ (• - • c - c

·[ l~ ·r ~ e ~~ -::::::

G) f~

~ ~

·~ ~·

'f f"' r r ·1 ·~ ~· 1> 'G\ b - <.e_ r. - <... ·~ -

' C 'l; ""' ) · , ~ , to c--:- ,<:.: I?S ·~ ·~· f c._ ~ !t c • ·I • 1::.. f..~ (. I .:: f:... ~ r ~ <o ~ ~ t ~. ~ 'l~~=~ ·.v 1> t b. 1 }; ~ C- t ..

I 0 l(i\ , I (._ - ~ I (o (s (_ I • 1 .. ~ ~ . ~ t ·~ ~··~:..l <c.. ~ - ~· ·t."( E ~~ ~ <o; ~<'. ~~ t , ~ b [: [ o-s (o f 1 - - ,\- f; :(:S

·C ~~ ).~ f E!

'-<> f:_ I ~ t • ' '!; (._ !;. 1 - ,. - '1,• sr ~ ~t ~~ r -:, ~·~ (_-;- :::: l r ~ ' C · - '"' '"' - ~ \.'-'=>"' -\r.:!l -I- .

-----------···- ·--·---·-··-·· ·---- .... - -·--

;~.1' ·:·,·.

~ .:·: i. ·:.,.

j~~

Osteomalacia 0 : .

-T Osteomalacia is rickets in adults and is frequently called "adult rickets~"

Normal adults rarely have a serious dietary deficiency of vitamin D or calcium because large quantities of calciuaJ are not needed for bone growth as in children. However, a seri­~us deficiency of both vitamin D and calcium occaslOriaTiy ~ .. occurs as a result of steatorrhea (failure to absorb fat), for vitamin D is fat-soluble, and calcium tends to form insolu­ble soaps with fat;: consequently, in steatorrhea ~Qth vita­min D and calciu~ tend to pass into the feces:X"Q~ these conditions an adult occasionally has such poor c~um and · phosphate absorption that adult rickets can occur, though this almost never proceeds to the stage of tetany- but very often is a ca1,1se of severe bone disability.

,I

(~ ~)

t '

r I .

I.'.

l~

.. ' ,f ,I

fliCKETS

.. ]:£.:~~.~_;, ,: ' . I •

~~~-t~>~ : ~~· . ~ . -/ ~~ , · .. ~~F£ ¥1t~1*' ·· ... W

. ;

... ---------- --·--------------···--·--······-----·-----------

~

~ CD ~§..occurs nwinly in children as a result o~ calcium or

plw.sph~t.e~eu.ciency in the extr~cell~lar fluid. YeLY, onJj .. nanly nckets 1s due to lack of v1tarnin D, rather t11nn a dietary lack of calcitunor phosphate. If the child is-properly exposed to sunlight, the 7 -dehydrocholesterol in the skin bec01nes activated by the ultraviolet rays <lnd forms vitamin D3 , ·which prevents rickets by promoting calcium and phon­phate absorption fron1 the intestines, as discussed earlier in Lhe chapter. .

tP.Chihlren who rernain indoors throu'gh the winter in gen­eral do not receive adequate quantities of yita~n D without some supplementary therapy in the diet~i2Kets tends to occur especially in the s·pring months because vitamin D fanned during the preceding summer is stored in the liver nnd is still available for use during the early winter monthfl, Also, calciUin and phosphate absorption from the bones can prevent clinical signs of rickets for the first few monthn of vitamin D deficiency.

. ... ~·

; j

\'-....._____--

'tt· ',' 'J''\""'"' ---.,._ .. -..,.~~ ;I

·-.- ... - .... ·-.--........ !111 ........ ,,.,,n,~·a 1

~\ ~.! i ',< i , ' I

• ' I 1 ·-..... / I ' ---'

d~sr£0POROSIS . ·. oJeOQ~tosis! ~he\ ffiost common of all. bone di·s;a_ses in

-· adul~s .-a~d especially in old age, & a different dr~e~se .··· froi:nloStecnnalacia and rickets, for ~eSults from d1mm­_ ished orga~ic 'mq..trix rather than abndrmal bone calci­~cat~ori. "(J§Ualty, in osteoPorosiS the osteoblastic activity

_In tJ.le bone is lesS than normal, and Consequently the ·rate lof bone deposition is depressed.0But occasionally, as illi hyPerparathy;roidism, the cause offhe diminished

'-~~l~e~c~~~ ~st_eoclastic activity. . __ -- - ----. -:-:-- - . . ! ~..... •-. •. ···- "'·-...::::.=::....-=~ I

)

•

~· ~;

\i

'

CAUSES OF OSTEOPOROSIS ARE:

1) Lack of physical stress on the bones because of

inactivity.

2) Malnutrition to the extent that sufficient protein

n1atrix cannot be forn1ed.

3) Lack ofvita1nin C,

4) Postlncnopausal lack of estrogen secretion.

5) Old age, in which 1nany ofthe protein anaboHc

functions are poor .

6) Cushing's disease, because 1nassive quantitjes

of glucocorticoids cause decreased deposition of

protein.

7) Acroinegaly, possibly because of lack of sec

honnones, excess of adrenocortical honnnes~

and often lack of insulin because of the

diabetogenic effect of growth hon11one.

(

PTHrP ~ [J PTH

~ /

ATP cAMP

Diacylglycerol

t Protein

kinase C activation

1 ,4,5-lnsP3

t Intracellular

calcium mobilization

FIGURE 23-7 Signal transduction pathways activat{:~ by PTH or PTHrP binding to the hPTH/hPTHrP receptor. lntracellt1lar cAMP is increased via Gs and adenylyl cyclase (AC). Diacylglycerol and IP3 {1 ,4,5-lnsP3) are increased via Gq and phospholipase C (Pl. C). (Modi­

fied and reproduced with permission from McPhee SJ, Lingappa VR, Ganong WF

[editors]: Pathophysiology of Disease, 4th ed. McGraw-Hill, 2003.)

MECHANISM OF ACTION

It no\v appears that there are at least three different PTH re tors. 0~ also binds parathyroid hormone-related (PTHrP; see below) and is known as the hPTH/PTHrP recepto

A_ ~econd receptor, PTH2 (hPTH2-R), does not bind PTHrP and is found in the brain, placenta, and pancreas. In addition, there is evidence for a third receptor, CPTH, which reacts with. the carboxyl terminal rather than the amino terminal of PTH. The first two receptors are coupled to G5 , and via this hetero­trimeric G protein they activate adenylyl cyclase, increasing intracellular cAMP. The hPTH/PTHrP receptor also activates PLC via Gq, increasing intracellular Ca2+ and activating pro­tein kinase C (Figure 23-7). However, the way these second messengers affect Ca2+ in bone is unsettled.

In the disease called pseudohypoparathyroidism, the signs and symptoms of hypoparathyroidism develop but the circu­lating level of PTH is normal or elevated. Because the tissues fail to respond to the hormone, this is a receptor disease. There are two forms. In _the mor~ common form, a congenital 50% reduction of the activity of G5 occurs and PTH fails to produce a normal increase· in cAMP concentration. In a dif­ferent, less common form, the cAMP response is normal but the phosphaturic action of the hormone is defective.

PTHrP

Another protein with PTH activity, parathyroid hormone­related protein (PTHrP), is produced by n1any different tis­sues in the body. It has 140 amino acid residues, compared with 84 in PTH, and is encoded by a gene on human chroino­son1e 12, whereas PTH is encoded by a gene on chromosorr1e 11. PTHrP and PTH have marked ho1nology at their amino terminal ends and they both bind to the hPTH/ PTHrP recep-· tor, yet their physiologic effects are very different. How is this possible when they bind to the same receptor? For one thing, PTHrP is primarily a paracrine factor, acting close to where it is produced. It may be that circulating PTH cannot reach at least some of these sites. Second, subtle conformational differ­ences may be produced by binding of PTH versus PTHrP to their receptor, despite their1 structural similarities. Another possibility is action of one or the other hormone on other, more selective receptors.

PTHrP has a marked effect on the growth and development of cartilage in utero. Mice in which both alleles of the PTHrP gene are knocked out have severe skeletal deformities and die soon after birth. In normal animals, on the other hand, PTHrP-stimulated cartilage cells proliferate and their termi­nal differentiation is inhibited. PTHrP is also expressed in the brain, where evidence indicates that it inhibits excitotoxic damage to developing neurons. In addition, there is evidence that it is involved in Ca2+ transport in the placenta. PTHr;J?Js also found in keratinocytes in the skin, in smooth muscle, and

in the teeth, where it is present in the enamel epithelium that caps each tooth. In the absence of PTHrP, teeth cannot erupt

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