Bone resorption and bone formation appear to be tightly coupled. To explore osteoclast influences on osteoblast recruitment and differentiation, we examined osteoclast conditioned media (CM) for influences on osteoblasts. Osteoclast CM stimulated human mesenchymal stem (hMS) cell mineralized nodule formation. We identified candidate osteoclast-derived coupling factors using Affymetrix microarray. We observed induction of sphingosine kinase 1 (SPHK1), WntlOb, and BMP6 in mature multinucleated osteoclasts as compared to pre-osteoclasts. Stimulation of hMS cell nodule formation by the osteoclast CM was attenuated by the Wnt antagonist, Dkk1, a BMP-6 neutralizing antibody, and by a S1P antagonist. Sclerostin expression was elevated in osteoclast precursors and rapidly down-regulated during differentiation. CM from osteoclasts generated in vitro from 18-month old mice was unable to support hMS cell mineralization. TGF-beta treatment elevated SPHK1 and WntlOb expression. Our central hypothesis is that osteoclast production of SPHK1, WntlOb, and BMP6, combined with decreased Sclerostin expression, promotes osteoblast precursor recruitment, proliferation, differentiation, and survival and that each factor plays an integral role in maintaining coupling between osteoclast-mediated bone resorption and osteoblast-mediated bone formation.
In Aim 1, we will use functional cell assays and gene expression to ascertain the mechanisms by which osteoclast-derived coupling factors promote osteoblast gene expression, recruitment, proliferation, differentiation, and survival in vitro.
In Aim 2 we will use molecular approaches to determine the mechanisms by which Sclerostin, SPHK1, WntlOb, and BMP6 are modulated during osteoclast differentiation in vitro.
In Aim 3 we will use an in vivo model to examine the role of TGF-beta regulation of coupling factor production on osteoclast-mediated coupling of bone resorption to bone formation.
In Aim 4 we will examine gene expression and cellular assays to resolve the contribution of age in osteoclast support of osteoblast maturation and mineralization. Together, these studies will provide important novel information on how osteoclasts control osteoblast-mediated bone formation.

Public Health Relevance

A crucial question in bone biology is how osteoblasts are recruited to a resorption site and how the amount of bone laid down is controlled. Studies have implicated osteoclasts as important modulators of bone formation. Understanding the mechanisms by which osteoclasts influence osteoblast recruitment, differentiation, and survival will likely lead to more effective theapies to selectively promote bone formation.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1-ZIJ-8)
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Mayo Clinic, Rochester
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Bower, James H; Grossardt, Brandon R; Rocca, Walter A et al. (2018) Prevalence of and indications for antipsychotic use in Parkinson's disease. Mov Disord 33:325-328
Rocca, Walter A; Grossardt, Brandon R; Brue, Scott M et al. (2018) Data Resource Profile: Expansion of the Rochester Epidemiology Project medical records-linkage system (E-REP). Int J Epidemiol 47:368-368j
Xu, Ming; Pirtskhalava, Tamar; Farr, Joshua N et al. (2018) Senolytics improve physical function and increase lifespan in old age. Nat Med 24:1246-1256
Khosla, Sundeep; Farr, Joshua N; Kirkland, James L (2018) Inhibiting Cellular Senescence: A New Therapeutic Paradigm for Age-Related Osteoporosis. J Clin Endocrinol Metab 103:1282-1290
Rocca, Walter A (2018) The future burden of Parkinson's disease. Mov Disord 33:8-9
Rocca, Walter A; Gazzuola Rocca, Liliana; Smith, Carin Y et al. (2018) Personal, reproductive, and familial characteristics associated with bilateral oophorectomy in premenopausal women: A population-based case-control study. Maturitas 117:64-77
Drake, Matthew T; Fenske, Jennifer S; Blocki, Frank A et al. (2018) Validation of a novel, rapid, high precision sclerostin assay not confounded by sclerostin fragments. Bone 111:36-43
Laughlin-Tommaso, Shannon K; Khan, Zaraq; Weaver, Amy L et al. (2018) Cardiovascular and metabolic morbidity after hysterectomy with ovarian conservation: a cohort study. Menopause 25:483-492
Farr, Joshua N; Weivoda, Megan M; Nicks, Kristy M et al. (2018) Osteoprotection Through the Deletion of the Transcription Factor Ror? in Mice. J Bone Miner Res 33:720-731
Wenning, Gregor; Trojanowski, John Q; Kaufmann, Horacio et al. (2018) Is multiple system atrophy an infectious disease? Ann Neurol 83:10-12

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