title: Replacement of bone marrow by bone in rat femurs: the bone bioreactor.
abstract: During development and repair of bone, two distinct yet complementary mechanisms, intramembranous and endochondral, mediate new bone formation via osteoblasts. Because mechanical bone marrow ablation leads to the rapid and transient formation of new bone in the marrow cavity, we postulated that parathyroid hormone (PTH), which is a bone anabolic hormone, enhances the formation of new bone that forms after marrow ablation. We subjected the left femur of rats to mechanical marrow ablation, or sham operation, and injected the animals daily with PTH or vehicle for 1, 2, or 3 weeks in a first experiment, then with PTH, parathyroid hormone-related peptide (PTHrP), or vehicle for 3 weeks in a second experiment. We subjected both femurs from each rat to soft X-ray, peripheral quantitative computed tomography, computed tomography on a microscale, and histological analysis, and determined the concentration of serum osteocalcin. In addition, in the second experiment, we determined the serum concentration of calcium, tartrate-resistant acid phosphatase (TRAP), and receptor activator of NF-kappaB ligand (RANKL) at 3 weeks, and subjected femurs to biomechanical testing. Following treatment with PTH or PTHrP for 3 weeks, bone filled the marrow cavity of the shafts whose marrow had been ablated. PTH increased trabecular density in the right femur, but failed to induce bone formation in the medullary region of the right unoperated femoral shafts. The newly formed bone endowed left femoral shafts with improved biomechanical properties when compared to those of right femurs and left femurs from control, sham-operated, and vehicle-treated rats. PTHrP, like PTH, increased serum osteocalcin, but neither increased serum calcium, TRAP, or RANKL at 3 weeks. Our results reveal that the newly formed bone that follows marrow ablation is responsive to PTH, expand the role of PTH in bone, and might open new avenues of investigations to the field of regenerative medicine and tissue engineering. Local bone marrow removal in conjunction with pharmacologic intervention with an anabolic agent might provide a technique for rapid preferential site-directed bone growth in areas of high bone loss.
authors.affiliation: Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Esteban
authors.initials: E
authors.lastname: Cuartas
authors.forename: Nozer
authors.initials: N
authors.lastname: Mehta
authors.forename: James
authors.initials: J
authors.lastname: Gilligan
authors.forename: Hua-Zhu
authors.initials: HZ
authors.lastname: Ke
authors.forename: W Mark
authors.initials: WM
authors.lastname: Saltzman
authors.forename: Maya
authors.initials: M
authors.lastname: Kotas
authors.forename: Mandy
authors.initials: M
authors.lastname: Ma
authors.forename: Sonali
authors.initials: S
authors.lastname: Rajan
authors.forename: Cécile
authors.initials: C
authors.lastname: Chalouni
authors.forename: Jodi
authors.initials: J
authors.lastname: Carlson
authors.forename: Agnès
authors.initials: A
authors.lastname: Vignery
mesh_terms: D000135:Acid Phosphatase / Q000097:blood; D000818:Animals; D019149:Bioreactors; D001846:Bone Development / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects / Q000601:surgery*; D001842:Bone and Bones; D002118:Calcium / Q000097:blood; D005269:Femur / Q000254:growth & development / Q000601:surgery*; D006801:Humans; D007527:Isoenzymes / Q000097:blood; D008297:Male; D010281:Parathyroid Hormone / Q000494:pharmacology; D044162:Parathyroid Hormone-Related Protein / Q000494:pharmacology; D053245:RANK Ligand / Q000097:blood; D051381:Rats; D000071681:Tartrate-Resistant Acid Phosphatase; D023822:Tissue Engineering / Q000379:methods*
chemical_list: D007527:Isoenzymes; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D053245:RANK Ligand; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D002118:Calcium