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Full-Length spp24, but Not Its 18.5-kDa Proteolytic Fragment, Inhibits Bone-Healing in a Rodent Model of Spine Fusion
Chananit Sintuu, PhD1; Robert J. Simon, BS2; Masashi Miyazaki, MD3; Yuichiro Morishita, MD3; Henry J. Hymanson, BS3; Cyrus Taghavi, BS3; Elsa J. Brochmann, PhD2; Samuel S. Murray, MD2; Jeffrey C. Wang, MD4
1 Biomedical Engineering Interdepartmental Program, School of Engineering and Applied Science, University of California Los Angeles, 5121 Engineering V, Los Angeles, CA 90095
2 Research Service (R.J.S.) and Geriatric Research, Education, and Clinical Center (E.J.B. and S.S.M.), VA Greater Los Angeles Healthcare System, 16111 Plummer Street, Sepulveda, CA 91343
3 Department of Orthopaedic Surgery, University of California Los Angeles, MacDonald Medical Research, Room 2-619, 675 Charles E. Young Drive, Los Angeles, CA 90095
4 UCLA Spine Center, 1250 16th Street, Suite 745, Santa Monica, CA 90404. E-mail address: jwang@mednet.ucla.edu
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Disclosure: One or more of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of an aspect of this work. In addition, one or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by the authors are always available with the online version of this article at jbjs.org.

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Investigation performed at University of California Los Angeles and VA Greater Los Angeles Healthcare System

Copyright © 2011 by The Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2011 Jun 01;93(11):1022-1032. doi: 10.2106/JBJS.J.00081
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Growth factors like bone morphogenetic protein (BMP) are used as bone-graft substitutes to enhance bone growth in clinical situations. However, adverse reactions have been associated with BMP use. We developed a synthetic adjuvant therapy based on the sequence of a BMP-binding protein, secreted phosphoprotein-24 (spp24), which enhances the effects of BMPs and ameliorates the adverse reactions. Our hypothesis is that a natural proteolytic fragment of spp24 is identical to an osteogenic protein previously described independently by two investigators. To test this hypothesis, spp24 and a truncated form of spp24 were separately implanted with recombinant human BMP-2 (rhBMP-2) in a rodent model of spine fusion.


Two isoforms of spp24 were constructed with use of DNA recombinant technology. Spp24 with or without rhBMP-2 were added to collagen sponges and implanted bilaterally between L4 and L5 transverse processes. Radiographs were made biweekly, and spines were explanted after eight weeks. Gross evaluation, microquantitative computed tomography study, and histological analysis were performed to evaluate bone growth.


Animals that received full-length spp24 and rhBMP-2 exhibited a complete obliteration of bone growth, while animals with the truncated form in combination with rhBMP-2 exhibited a mild inhibition to bone growth, with bone area measured from radiographs. Manual assessment and gross evaluation of all spines confirmed the results obtained from the bone-area measurements. Microquantitative computed tomography provided three-dimensional visual images of representative specimens, while histological staining of spine tissue displayed cellular evidence of bone formation.


Results from this investigation confirm that the various isoforms of spp24 affect the bone-healing activity of rhBMP-2 in the rat spine fusion model. Thus, proteolytic modification of this protein is a likely mechanism for the regulation of BMP availability in the physiological environment. Future studies will define the roles of these proteins in controlling the activity of BMPs and other members of the transforming growth factor-beta family of cytokines. This information will increase the understanding of normal bone-healing, allowing for the engineering of more effective orthopaedic treatment.

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    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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