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Chemokine and Chemokine Receptor Expression During Colony Stimulating Factor-1-Induced Osteoclast Differentiation in the Toothle

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Chemokine and Chemokine Receptor Expression During Colony Stimulating Factor-1-Induced Osteoclast Differentiation in the Toothle University of Massachusetts Medical School eScholarship@UMMS Open Access Articles Open Access Publications by UMMS Authors 2005-11-24 Chemokine and chemokine receptor expression during colony stimulating factor-1-induced osteoclast differentiation in the toothless osteopetrotic rat: a key role for CCL9 (MIP-1gamma) in osteoclastogenesis in vivo and in vitro Meilheng Yang University of Massachusetts Medical School Et al. Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/oapubs Part of the Cell Biology Commons Repository Citation Yang M, Mailhot G, MacKay CA, Mason-Savas A, Aubin J, Odgren PR. (2005). Chemokine and chemokine receptor expression during colony stimulating factor-1-induced osteoclast differentiation in the toothless osteopetrotic rat: a key role for CCL9 (MIP-1gamma) in osteoclastogenesis in vivo and in vitro. Open Access Articles. https://doi.org/10.1182/blood-2005-08-3365. Retrieved from https://escholarship.umassmed.edu/oapubs/275 This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in Open Access Articles by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. CHEMOKINES, CYTOKINES, AND INTERLEUKINS Chemokine and chemokine receptor expression during colony stimulating factor-1–induced osteoclast differentiation in the toothless osteopetrotic rat: a key role for CCL9 (MIP-1␥) in osteoclastogenesis in vivo and in vitro Meiheng Yang, Genevie`ve Mailhot, Carole A. MacKay, April Mason-Savas, Justin Aubin, and Paul R. Odgren Osteoclasts differentiate from hematopoi- peared on day 2, peaked on day 4, and oclasts on day 2 and in mature cells at etic precursors under systemic and local decreased slightly on day 6, as marrow later times. Anti-CCL9 antibody inhibited controls. Chemokines and receptors di- space was expanding. TRAP and cathep- osteoclast differentiation in culture and rect leukocyte traffic throughout the body sin K mRNA paralleled the cell counts. We significantly suppressed the osteoclast and may help regulate site-specific bone examined all chemokine and receptor response in CSF-1–treated tl/tl rats. While resorption. We investigated bone gene mRNAs on the arrays. CCL9 was strongly various chemokines have been impli- expression in vivo during rapid oste- induced and peaked on day 2, as did its cated in osteoclastogenesis in vitro, this oclast differentiation induced by colony- receptor, CCR1, and regulatory receptors first systematic analysis of chemokines stimulating factor 1 (CSF-1) in Csf1-null c-Fms (CSF-1 receptor) and RANK (recep- and receptors during osteoclast differen- toothless (tl/tl) rats. Long-bone RNA from tor activator of nuclear factor ␬B). Other tiation in vivo highlights the key role of CSF-1–treated tl/tl rats was analyzed by chemokines and receptors showed little CCL9 in this process. (Blood. 2006;107: high-density microarray over a time or no significant changes. In situ hybrid- 2262-2270) course. TRAP (tartrate-resistant acid ization and immunohistochemistry re- phosphatase)–positive osteoclasts ap- vealed CCL9 in small, immature oste- © 2006 by The American Society of Hematology Introduction Osteoclasts are specialized, multinucleated bone-resorbing cells family member, RANKL (also called TRANCE, OPGL, or TN- that differentiate by fusion of mononuclear hematopoietic precur- FSF11), which are supplied in the skeleton by osteoblasts. Follow- sor cells of the myeloid lineage. This complex process is closely ing CSF-1 and RANKL binding, precursor cells fuse and become regulated and requires numerous systemic and local factors, multinucleated, attach to bone, differentiate, and become active, including growth factors, hormones, transcription factors, en- bone-resorbing cells. One naturally occurring osteopetrotic model zymes, and transporters for resorption to occur at the necessary is the toothless (tl/tl) rat,5,6 an autosomal recessive mutation in levels and appropriate skeletal sites. The anabolic and catabolic which a frameshift in the CSF-1 gene causes severe osteopetrosis activities of osteoblasts, osteocytes, and osteoclasts are normally due a virtually complete lack of osteoclasts.7,8 Injections of soluble, exquisitely balanced to maintain normal bone mass.1 Excessive recombinant CSF-1 rapidly restore osteoclast populations and resorptive activity causes bone deficiency, for example in osteopo- rescue many, but not all, aspects of the phenotype.9-11 rosis, arthritis, or other bone-loss syndromes, whereas defective While cell and organ culture models are essential experimental resorptive activity can cause osteopetrosis, characterized by dense, tools, no ex vivo system can replicate the complex interactions that brittle bones, lack of marrow cavities, and lack of teeth due to occur in living bone. The CSF-1-treated tlCsf1/tlCsf rat thus provides blockage of eruption.2 a powerful model to study molecular and cellular events that There are many known mutations in human patients and in accompany osteoclastogenesis in vivo. We used high-density animal models that inhibit osteoclastogenesis and/or osteoclast microarrays to investigate gene expression changes that occur in activity.3,4 Each of these osteopetrotic mutations has provided the tibia during the burst of osteoclastogenesis caused by CSF-1 insights into mechanisms that regulate the differentiation and injections in the tl/tl rat. One gene that was very highly up- activity of osteoclasts. Two growth factors essential for early steps regulated was the chemokine CCL9 (also called MIP-1␥, CCF18, in the commitment of F4/80-positive, mononuclear leukocytes to Scya9, or MRP-2).12 Recent cell culture studies by several differentiate along the osteoclast pathway are colony stimulating groups13-17 suggest that chemokines and their receptors could play factor-1 (CSF-1, or M-CSF) and the tumor necrosis factor (TNF) roles in extravasation, migration, and/or survival of osteoclastic From the Department of Cell Biology, University of Massachusetts Medical M.Y. performed research, designed project, designed experiments, and wrote School, Worcester, MA. the paper; G.M., C.A.M., A.M.-S., and J.A. performed research; and P.R.O. performed research, designed the project, designed research, and wrote the Submitted August 18, 2005; accepted November 7, 2005. Prepublished online paper. as Blood First Edition Paper, November 22, 2005; DOI 10.1182/blood-2005-08- 3365. Reprints: Paul R. Odgren, Dept of Cell Biology, S7-242, 55 Lake Ave, North Worcester, MA 01655; e-mail: [email protected]. Supported by grants DE 07444 and DE13961 from the National Institute of The publication costs of this article were defrayed in part by page charge Dental and Craniofacial Research (NIDCR) to P.R.O. and by core facilities payment. Therefore, and solely to indicate this fact, this article is hereby support from the Diabetes Endocrinology Research Center grant DK32520 marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734. from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD). © 2006 by The American Society of Hematology 2262 BLOOD, 15 MARCH 2006 ⅐ VOLUME 107, NUMBER 6 BLOOD, 15 MARCH 2006 ⅐ VOLUME 107, NUMBER 6 CCL9 IN OSTEOCLASTOGENESIS 2263 cells in vivo. In addition, CCL3 (MIP-1␣) has been implicated in carefully dissected to remove extraneous connective tissue and muscle, and local osteolysis due to myeloma18 and prosthesis wear particles.19 joint cartilage and epiphyseal growth plates were also removed, leaving the Chemokines are a large family of small, secreted (with very few metaphysis and diaphysis. Bones were split longitudinally and flushed with exceptions) proteins that regulate the migration and interactions cold phosphate-buffered saline (PBS) to remove as much marrow as possible, although in untreated and 2-day-treated mutants, no discernible of white blood cells of all types.20-22 Their receptors are also marrow spaces had formed. Dissected bones were flash-frozen in liquid numerous: some can bind more than one chemokine, and vice nitrogen for later RNA extraction. For studies of in vivo inhibition of versa. This produces some redundancies and overlap of functions. osteoclast differentiation by anti-CCL9, tl/tl rats were injected at 20 days Chemokines are categorized structurally based on the arrangement after birth with 50 ␮g affinity-purified rabbit anti-murine CCL9 (MIP-1␥) of N-terminal region Cys residues. CC denotes adjacent cysteines antibody (Peprotech, Rocky Hill, NJ) in 100 ␮L PBS, and again on days 21 and CX(N)C denotes a residue (or the number of residues) between and 23, with 50 ␮g anti-CCL9 plus 106 U CSF-1 in 100 ␮L PBS. On them. They are also characterized as “homeostatic” or “inflamma- alternate days, they received only CSF-1, as described. tory,” depending on whether they participate in the normal regulation of leukocyte differentiation and targeting or are mainly Osteoclast counts involved in inflammatory responses. Some are known as “dual- 20 Contralateral tibiae were dissected from animals used in the CSF-1 time function” chemokines, participating in both processes. The course, immersion-fixed in glutaraldehyde and paraformaldehyde, deminer- chemokine receptors are named by the structural category of their alized in EDTA, embedded in glycol methacrylate, and processed for TRAP ligands, followed by a number. For example, CCR1 is the first (tartrate-resistant acid phosphatase) histochemistry to visualize osteoclasts member
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