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Parathyroid Hormone Stimulates Bone Formation and Resorption In Proc. Nati. Acad. Sci. USA Vol. 78, No. 5, pp. 3204-3208, May 1981 Medical Sciences Parathyroid hormone stimulates bone formation and resorption in organ culture: Evidence for a coupling mechanism (endocrine/mineralization/bone metabolism/cartilage/regulation) GuY A. HOWARD, BRIAN L. BOTTEMILLER, RUSSELL T. TURNER, JEANNE I. RADER, AND DAVID J. BAYLINK American Lake VA Medical Center, Tacoma, Washington 98493; and Department of Medicine, University of Washington, Seattle, Washington 98195 Communicated by Clement A. Finch, January 26, 1981 ABSTRACT We have developed an in vitro system, using em- growing rats with PTH results in an increase in formation and bryonic chicken tibiae grown in a serum-free medium, which ex- resorption (4) and a net gain in bone volume (10-12). We have hibits simultaneous bone formation and resorption. Tibiae from recently obtained similar results in vitro for the acute and 8-day embryos increased in mean (±SD) length (4.0 ± 0.4 to 11.0 chronic effects of PTH (13). Moreover, as reported earlier for ± 0.3 mm) and dry weight (0.30 ± 0.04 to 0.84 ± 0.04 mg) during resorption in rat bone (14), the in vitro effect of PTH in our 12 days in vitro. There was increased incorporation of [3H]proline system is an inductive one in that the continued presence of into hydroxyproline (120 ± 20 to 340 ± 20 cpm/mg of bone per PTH is unnecessary for bone resorption and bone formation to 24 hr) as a measure of collagen synthesis, as well as a 62 ± 5% increase in total calcium and 45Ca taken up as an indication of ac- be stimulated for several days (13). tive mineralization. A physiologic concentration (1 pM) of para- Our hypothesis for these findings is that some type ofinher- thyroid hormone was found to stimulate bone resorption over con- ent bone regulation not requiring the continued presence of trol levels in this system. Parathyroid hormone stimulated the PTH could explain the apparently divergent effects of PTH on release of [3H]hydroxyproline from the bone shafts but not from bone formation. Accordingly, the ability ofPTH to induce bone the cartilage ends, indicating the specificity oftheresponse. With resorption under chronic conditions could enhance the synthe- 1 pM parathyroid hormone we observed an acute inhibition of sis or release of a substance that subsequently was stimulatory bone formation, followed (after 12-16 hr) by a chronic stimulation for bone formation. This is consistent with the concept of an of bone formation during the 12-day incubation. Both mineral osteogenic coupling factor that could be involved in the local uptake and matrix formation were enhanced at approximately the regulation of endosteal bone volume as is observed in vivo (3, same rate during the 12-day incubation. The chronic enhancement 4). The in vitro system described herein was used to test this of formation required parathyroid hormone only for the initial hypothesis. 8-10 hr of incubation. These results could be explained by the production or release ofa factor from bone to stimulate formation MATERIALS AND METHODS in response to the acute increase in resorption-a "coupling fac- Embryonic Bones. Fertilized Rhode Island Red chicken eggs tor." Indeed, dialyzed culture medium conditioned by actively (Fors Farms, Tacoma, WA) were incubated at 370C for 8 days, resorbing bones stimulated bone formation over controls when at which time the embryos were removed from the eggs. The added to organ cultures at a 1:20 dilution. The factor is larger than tibiae and femora were isolated by blunt dissection and de- 12,000 daltons as determined by dialysis. The factor is specific for brided of soft tissue by gently rolling the bones on dry sterile the bone shaft and did not affect the cartilage ends. gauze. Isolated bones were rinsed three times in Hanks' bal- Work directed toward a better understanding ofthe regulation anced salt solution and then transferred to lens paper rafts, two of bone metabolism has shown that bone formation and bone bones per raft, with 0.5 ml of medium (13, 15). resorption are coupled in vivo (1). This coupling occurs even Culture Conditions. The embryonic bones were cultured in in some disease states (e.g., hyper- and hypoparathyroidism, vitro at 370C in a moist atmosphere of5% CO2 in air. The basic Paget disease, and acromegaly) (2). Detailed knowledge of the medium for control incubation conditions was Fitton-Jackson regulatory mechanism of coupling could lead to better under- modified BGJb medium (GIBCO) containing added potassium standing of the problems of metabolic bone disease. Studies phosphate (4.8 mM, final phosphate concentration) and non- toward this end from our laboratory have in the past relied pre- radioactive proline (3.4 mM, final concentration). The medium dominantly on in vivo experiments (3, 4). Although a large num- was changed every second day, unless otherwise indicated. ber of investigators have examined bone metabolism in vitro Bone Formation and Resorption. Bone formation was eval- (5-9), none of these studies involved a chemically defined sys- uated by measuring total length, dry weight, incorporation of tem in which simultaneously enhanced bone formation and re- [3H]proline into collagen as [3H]hydroxyproline, incorporation sorption could be demonstrated. We have developed such an of45Ca, and total calcium content. Bone resorption was assessed in vitro system and describe the details herein. by quantification of ["H]hydroxyproline released into the cul- We have utilized this coupled system to study the effects of ture medium from bones which had been incubated previously parathyroid hormone (PTH) on bone metabolism in vitro in an with [3H]proline (13, 16). Specifically, bones were incubated attempt to clarify what appears to be a disagreement in the lit- for 24 hr in the presence of[3H]proline to label the collagen hy- erature concerning these effects. The acute effect in vivo is re- droxyproline. The bones were then cultured for an additional ported to be the stimulation of bone resorption and inhibition 24 hr in control medium in the absence of added [3H]proline ofbone formation (10, 11). Chronic in vivo treatment of young to allow the soluble radioactivity to be either incorporated into matrix collagen (13, 16) or washed away. The medium was then The publication costs ofthis article were defrayed in part by page charge replaced with control or test medium and the subsequent re- payment. This article must therefore be hereby marked "advertise- ment" in accordance with 18 U. S. C. §1734 solely to indicate this fact. Abbreviations: PTH, parathyroid hormone; PTE, parathyroid extract. 3204 Downloaded by guest on September 27, 2021 Medical Sciences: Howardet al. Proc. Natl. Acad. Sci. USA 78 (1981) 3205 lease of [3H]hydroxyproline into the medium was determined Growth of the embroyonic bones in vitro under control in- as a function of incubation time. cubation conditions involved an increase in mineral content as Determination of [3H]Proline and 45Ca Incorporation. The well as formation ofnew matrix. A linear relationship was found bones were labeled for the last 24-48 hr ofthe 12-day incubation between 40Ca content and length of the bones (slope, 0.54) as period with [3H]proline (L-[2,3-3H]proline; Amersham; 21.8 well as between 40Ca content and dry weight ofthe bones (slope, mCi/mg; 1 Ci = 3.7 x 1010 becquerels). After removal from 6.76). Both relationships showed statistically significant corre- the culture medium, the bones were rinsed thoroughly in three lations (r = 0.97; P <0.001). changes of balanced salt solution to remove exchangeable ra- We next examined the effect of a physiologic concentration dioactivity. The cartilage ends were dissected free from the shaft of PTE on bone resorption in this system. The results showed ofthe bone and combined in one test tube; the shaft was placed a significant simulation of bone resorption with 1 pM PTE (a in another. The samples were extracted for 5 min with 95% physiologic concentration for humans) over bones incubated in ethanol and then for 5 min with diethyl ether, air dried, and control medium, as assessed by the release of previously in- weighed on a microbalance. The bone shafts and cartilage ends corporated [3H]hydroxyproline into the culture medium (Fig. were hydrolyzed overnight in 0.2 ml of6 M HCl at 100'C; then 1). 'Ca or [3H]proline and [3H]hydroxyproline radioactivity were To examine the response of bone formation to PTE in our determined in a liquid scintillation spectrometer. system we tested the effect of different concentrations of PTE In order to quantify the radioactivity in proline and hydroxy- added to the control medium. We were able to show enhanced proline, they were separated on silica gel thin-layer plates (Po- bone formation, as assessed by [3H]hydroxyproline content, lygram Sil G, Brinkmann) by using distilled water as the solvent. with a physiologic concentration (1 pM) ofPTE (Fig. 2). At 0.01 Proline and hydroxyproline were separated from each other, as to 1 nM added PTE there was inhibition ofbone formation. We well as from arginine and glutamine, the other metabolites of used 1 pM PTE in the remainder of the studies on enhanced proline that could have been radioactively labeled. The amino bone formation because this concentration induced apparently acids were located by reaction with ninhydrin in acetone- (13). maximal stimulation of matrix formation over control bones The recoveries of radioactivity from the gel were >90%. The within the range of concentrations tested. same basic procedure was used to determine [3H]proline and Because the resorptive effect of PTH is reportedly on bone [3H]hydroxyproline released into the culture medium in the and not cartilage (18, 19), we tested to determine if this differ- resorption experiments, except that an equal volume of 10 M ence manifested itself in our in vitro system.
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