Bio

Clinical Focus


  • Endocrinology
  • Metabolic Bone Disease
  • Osteoporosis
  • Diabetes andMetabolism

Academic Appointments


Honors & Awards


  • Cancer Grant Recipient, The Mary Kay Foundation (2013 - 2015)
  • NIH Director's New Innovator Award, NIH (2011 - 2016)
  • Clinical Scientist Program Instructor Development Award, Harvard Stem Cell Institute (2009 - 2011)
  • Claflin Distinguished Scholar Award, Massachusetts General Hospital (2009 - 2011)
  • John Haddad Young Investigator Award, Advances in Mineral Metabolism (2008)
  • Merck Senior Fellow Award, The Endocrine Society (2007)
  • Young Investigator Award, American Society for Bone and Mineral Research Annual Meeting (2006)
  • Endocrine Scholars Award, The Endocrine Society (2006)
  • Alpha Omega Alpha, Duke University School of Medicine (1997)
  • Phi Beta Kappa, Stanford University (1993)
  • Marsden Memorial Award in Chemistry, Stanford University (1993)

Professional Education


  • Board Certification: Endocrinology, Diabetes andMetabolism, American Board of Internal Medicine (2006)
  • Fellowship:Massachusetts General Hospital (2006) MA
  • Board Certification: Internal Medicine, American Board of Internal Medicine (2004)
  • Residency:Brigham and Women's Hospital Harvard Medical School (2003) MA
  • Medical Education:Duke University School of Medicine (2001) NC
  • MD/PhD, Duke University (2001)

Research & Scholarship

Current Research and Scholarly Interests


As a physician scientist with a clinical focus on osteoporosis, my laboratory focuses on the mechanisms guiding the differentiation of mesenchymal stem cells, and how mesenchymal lineages support hematopoiesis in the bone marrow. In particular we are interested in the pathways that regulate the differentiation of mesenchymal progenitors into osteoblast and adipocyte lineages, using genetically modified mice and lineage tracing techniques in vivo. We are also studying the role of the osteoblast niche in supporting hematopoietic stem cell and B lymphocyte development, in both animal models as well as translational studies in humans. Finally, my laboratory is using induced pluripotent stem cells to study osteoblast differentiation in a skeletal complementation model in vivo.

Teaching

2013-14 Courses


Postdoctoral Advisees


Graduate and Fellowship Programs


Publications

Journal Articles


  • Teriparatide (PTH 1-34) Treatment Increases Peripheral Hematopoietic Stem Cells in Postmenopausal Women. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research Yu, E. W., Kumbhani, R., Siwila-Sackman, E., Delelys, M., Preffer, F. I., Leder, B. Z., Wu, J. Y. 2014

    Abstract

    Cells of the osteoblast lineage play an important role in regulating the hematopoietic stem cell (HSC) niche and early B cell development in animal models, perhaps via parathyroid hormone (PTH) dependent mechanisms. There are few human clinical studies investigating this phenomenon. We studied the impact of long-term daily teriparatide (PTH 1-34) treatment on cells of the hematopoietic lineage in postmenopausal women. Twenty-three postmenopausal women at high risk of fracture received teriparatide 20 mcg SC daily for 24 months as part of a prospective longitudinal trial. Whole blood measurements were obtained at baseline, 3, 6, 12, and 18 months. Flow cytometry was performed to identify hematopoietic subpopulations, including HSCs (CD34 + /CD45(moderate); ISHAGE protocol) and early transitional B cells (CD19 + , CD27-, IgD + , CD24[hi], CD38[hi]), CD38[hi]). Serial measurements of spine and hip bone mineral density as well as serum P1NP, osteocalcin, and CTX were also performed. The average age of study subjects was 64 ± 5. We found that teriparatide treatment led to an early increase in circulating HSC number of 40% ± 14% (p = 0.004) by month 3, which persisted to month 18 before returning to near baseline by 24 months. There were no significant changes in transitional B cells or total B cells over the course of the study period. In addition, there were no differences in complete blood count profiles as quantified by standard automated flow cytometry. Interestingly, the peak increase in HSC number was inversely associated with increases in bone markers and spine BMD. Daily teriparatide treatment for osteoporosis increases circulating HSCs by 3 to 6 months in postmenopausal women. This may represent a proliferation of marrow HSCs or increased peripheral HSC mobilization. This clinical study establishes the importance of PTH in the regulation of the HSC niche within humans. © 2014 American Society for Bone and Mineral Research.

    View details for DOI 10.1002/jbmr.2171

    View details for PubMedID 24420643

  • Differential regulation of myeloid leukemias by the bone marrow microenvironment. Nature medicine Krause, D. S., Fulzele, K., Catic, A., Sun, C. C., Dombkowski, D., Hurley, M. P., Lezeau, S., Attar, E., Wu, J. Y., Lin, H. Y., Divieti-Pajevic, P., Hasserjian, R. P., Schipani, E., Van Etten, R. A., Scadden, D. T. 2013; 19 (11): 1513-1517

    Abstract

    Like their normal hematopoietic stem cell counterparts, leukemia stem cells (LSCs) in chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML) are presumed to reside in specific niches in the bone marrow microenvironment (BMM) and may be the cause of relapse following chemotherapy. Targeting the niche is a new strategy to eliminate persistent and drug-resistant LSCs. CD44 (refs. 3,4) and interleukin-6 (ref. 5) have been implicated previously in the LSC niche. Transforming growth factor-β1 (TGF-β1) is released during bone remodeling and plays a part in maintenance of CML LSCs, but a role for TGF-β1 from the BMM has not been defined. Here, we show that alteration of the BMM by osteoblastic cell-specific activation of the parathyroid hormone (PTH) receptor attenuates BCR-ABL1 oncogene-induced CML-like myeloproliferative neoplasia (MPN) but enhances MLL-AF9 oncogene-induced AML in mouse transplantation models, possibly through opposing effects of increased TGF-β1 on the respective LSCs. PTH treatment caused a 15-fold decrease in LSCs in wild-type mice with CML-like MPN and reduced engraftment of immune-deficient mice with primary human CML cells. These results demonstrate that LSC niches in CML and AML are distinct and suggest that modulation of the BMM by PTH may be a feasible strategy to reduce LSCs, a prerequisite for the cure of CML.

    View details for DOI 10.1038/nm.3364

    View details for PubMedID 24162813

  • Myelopoiesis is regulated by osteocytes through Gsa-dependent signaling. Blood Fulzele, K., Krause, D. S., Panaroni, C., Saini, V., Barry, K. J., Liu, X., Lotinun, S., Baron, R., Bonewald, L., Feng, J. Q., Chen, M., Weinstein, L. S., Wu, J. Y., Kronenberg, H. M., Scadden, D. T., Divieti Pajevic, P. 2013; 121 (6): 930-939

    Abstract

    Hematopoietic progenitors are regulated in their respective niches by cells of the bone marrow microenvironment. The bone marrow microenvironment is composed of a variety of cell types, and the relative contribution of each of these cells for hematopoietic lineage maintenance has remained largely unclear. Osteocytes, the most abundant yet least understood cells in bone, are thought to initiate adaptive bone remodeling responses via osteoblasts and osteoclasts. Here we report that these cells regulate hematopoiesis, constraining myelopoiesis through a Gs?-mediated mechanism that affects G-CSF production. Mice lacking Gs? in osteocytes showed a dramatic increase in myeloid cells in bone marrow, spleen, and peripheral blood. This hematopoietic phenomenon was neither intrinsic to the hematopoietic cells nor dependent on osteoblasts but was a consequence of an altered bone marrow microenvironment imposed by Gs? deficiency in osteocytes. Conditioned media from osteocyte-enriched bone explants significantly increased myeloid colony formation in vitro, which was blocked by G-CSF–neutralizing antibody, indicating a critical role of osteocyte-derived G-CSF in the myeloid expansion.

    View details for DOI 10.1182/blood-2012-06-437160

    View details for PubMedID 23160461

  • G(s)alpha enhances commitment of mesenchymal progenitors to the osteoblast lineage but restrains osteoblast differentiation in mice JOURNAL OF CLINICAL INVESTIGATION Wu, J. Y., Aarnisalo, P., Bastepe, M., Sinha, P., Fulzele, K., Selig, M. K., Chen, M., Poulton, I. J., Purton, L. E., Sims, N. A., Weinstein, L. S., Kronenberg, H. M. 2011; 121 (9): 3492-3504

    Abstract

    The heterotrimeric G protein subunit Gs? stimulates cAMP-dependent signaling downstream of G protein-coupled receptors. In this study, we set out to determine the role of Gs? signaling in cells of the early osteoblast lineage in vivo by conditionally deleting Gs? from osterix-expressing cells. This led to severe osteoporosis with fractures at birth, a phenotype that was found to be the consequence of impaired bone formation rather than increased resorption. Osteoblast number was markedly decreased and osteogenic differentiation was accelerated, resulting in the formation of woven bone. Rapid differentiation of mature osteoblasts into matrix-embedded osteocytes likely contributed to depletion of the osteoblast pool. In addition, the number of committed osteoblast progenitors was diminished in both bone marrow stromal cells (BMSCs) and calvarial cells of mutant mice. In the absence of Gs?, expression of sclerostin and dickkopf1 (Dkk1), inhibitors of canonical Wnt signaling, was markedly increased; this was accompanied by reduced Wnt signaling in the osteoblast lineage. In summary, we have shown that Gs? regulates bone formation by at least two distinct mechanisms: facilitating the commitment of mesenchymal progenitors to the osteoblast lineage in association with enhanced Wnt signaling; and restraining the differentiation of committed osteoblasts to enable production of bone of optimal mass, quality, and strength.

    View details for DOI 10.1172/JCI46406

    View details for Web of Science ID 000294753700017

    View details for PubMedID 21804192

  • Role of the Osteoblast Lineage in the Bone Marrow Hematopoietic Niches JOURNAL OF BONE AND MINERAL RESEARCH Wu, J. Y., Scadden, D. T., Kronenberg, H. M. 2009; 24 (5): 759-764

    View details for DOI 10.1359/JBMR.090225

    View details for Web of Science ID 000265550000001

    View details for PubMedID 19257832

  • Osteoblastic regulation of B lymphopoiesis is mediated by G(s)alpha-dependent signaling pathways PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Wu, J. Y., Purton, L. E., Rodda, S. J., Chen, M., Weinstein, L. S., McMahon, A. P., Scadden, D. T., Kronenberg, H. M. 2008; 105 (44): 16976-16981

    Abstract

    Osteoblasts play an increasingly recognized role in supporting hematopoietic development and recently have been implicated in the regulation of B lymphopoiesis. Here we demonstrate that the heterotrimeric G protein alpha subunit G(s)alpha is required in cells of the osteoblast lineage for normal postnatal B lymphocyte production. Deletion of G(s)alpha early in the osteoblast lineage results in a 59% decrease in the percentage of B cell precursors in the bone marrow. Analysis of peripheral blood from mutant mice revealed a 67% decrease in the number of circulating B lymphocytes by 10 days of age. Strikingly, other mature hematopoietic lineages are not decreased significantly. Mice lacking G(s)alpha in cells of the osteoblast lineage exhibit a reduction in pro-B and pre-B cells. Furthermore, interleukin (IL)-7 expression is attenuated in G(s)alpha-deficient osteoblasts, and exogenous IL-7 is able to restore B cell precursor populations in the bone marrow of mutant mice. Finally, the defect in B lymphopoiesis can be rescued by transplantation into a WT microenvironment. These findings confirm that osteoblasts are an important component of the B lymphocyte niche and demonstrate in vivo that G(s)alpha-dependent signaling pathways in cells of the osteoblast lineage extrinsically regulate bone marrow B lymphopoiesis, at least partially in an IL-7-dependent manner.

    View details for DOI 10.1073/pnas.0802898105

    View details for Web of Science ID 000260913800034

    View details for PubMedID 18957542

  • Mesenchymal progenitors and the osteoblast lineage in bone marrow hematopoietic niches. Current osteoporosis reports Panaroni, C., Tzeng, Y., Saeed, H., Wu, J. Y. 2014; 12 (1): 22-32

    Abstract

    The bone marrow cavity is essential for the proper development of the hematopoietic system. In the last few decades, it has become clear that mesenchymal stem/progenitor cells as well as cells of the osteoblast lineage, besides maintaining bone homeostasis, are also fundamental regulators of bone marrow hematopoiesis. Several studies have demonstrated the direct involvement of mesenchymal and osteoblast lineage cells in the maintenance and regulation of supportive microenvironments necessary for quiescence, self-renewal and differentiation of hematopoietic stem cells. In addition, specific niches have also been identified within the bone marrow for maturing hematopoietic cells. Here we will review recent findings that have highlighted the roles of mesenchymal progenitors and cells of the osteoblast lineage in regulating distinct stages of hematopoiesis.

    View details for DOI 10.1007/s11914-014-0190-7

    View details for PubMedID 24477415

  • The PTH-Gαs-PKA cascade controls αNAC localization to regulate bone mass. Molecular and cellular biology Pellicelli, M., Miller, J. A., Arabian, A., Gauthier, C., Akhouayri, O., Wu, J. Y., Kronenberg, H. M., St-Arnaud, R. 2014

    Abstract

    The binding of PTH to its receptor induces Gαs-dependent cAMP accumulation to turn on effector kinases, including protein kinase A (PKA). The phenotype of mice with osteoblasts specifically deficient for Gαs is mimicked by a mutation leading to cytoplasmic retention of the transcriptional coregulator αNAC, suggesting that Gαs and αNAC form part of a common genetic pathway. We show that treatment of osteoblasts with PTH(1-34) or the PKA-selective activator 6Bnz-cAMP lead to translocation of αNAC to the nucleus. αNAC was phosphorylated by PKA at serine 99 in vitro. Phospho-S99-αNAC accumulated in osteoblasts exposed to PTH(1-34) or 6Bnz-cAMP but not in treated cells expressing dominant negative PKA. Nuclear accumulation was abrogated by an S99A mutation but enhanced by a phosphomimetic residue (S99D). ChIP analysis showed that PTH(1-34) or 6Bnz-cAMP treatment leads to accumulation of αNAC at the Osteocalcin (Ocn) promoter. Altered gene dosage for Gαs and αNAC in compound heterozygous mice results in reduced bone mass, increased numbers of osteocytes, and enhanced expression of Sost. Our results show that αNAC is a substrate of PKA following PTH signaling. This enhances αNAC translocation to the nucleus and leads to its accumulation at target promoters to regulate transcription and affect bone mass.

    View details for DOI 10.1128/MCB.01434-13

    View details for PubMedID 24550008

  • Interactions between B lymphocytes and the osteoblast lineage in bone marrow. Calcified tissue international Panaroni, C., Wu, J. Y. 2013; 93 (3): 261-268

    Abstract

    The regulatory effects of the immune system on the skeleton during homeostasis and activation have been appreciated for years. In the past decade it has become evident that bone tissue can also regulate immune cell development. In the bone marrow, the differentiation of hematopoietic progenitors requires specific microenvironments, called "niches," provided by various subsets of stromal cells, many of which are of mesenchymal origin. Among these stromal cell populations, cells of the osteoblast lineage serve a supportive function in the maintenance of normal hematopoiesis, and B lymphopoiesis in particular. Within the osteoblast lineage, distinct differentiation stages exert differential regulatory effects on hematopoietic development. In this review we will highlight the critical role of osteoblast progenitors in the perivascular B lymphocyte niche.

    View details for DOI 10.1007/s00223-013-9753-3

    View details for PubMedID 23839529

  • Potent constitutive cyclic AMP-generating activity of XL alpha s implicates this imprinted GNAS product in the pathogenesis of McCune-Albright Syndrome and fibrous dysplasia of bone BONE Mariot, V., Wu, J. Y., Aydin, C., Mantovani, G., Mahon, M. J., Linglart, A., Bastepe, M. 2011; 48 (2): 312-320

    Abstract

    Patients with McCune-Albright syndrome (MAS), characterized primarily by hyperpigmented skin lesions, precocious puberty, and fibrous dyslasia of bone, carry postzygotic heterozygous mutations of GNAS causing constitutive cAMP signaling. GNAS encodes the ?-subunit of the stimulatory G protein (Gs?), as well as a large variant (XL?s) derived from the paternal allele. The mutations causing MAS affect both GNAS products, but whether XL?s, like Gs?, can be involved in the pathogenesis remains unknown. Here, we investigated biopsy samples from four previously reported and eight new patients with MAS. Activating mutations of GNAS (Arg201 with respect to the amino acid sequence of Gs?) were present in all the previously reported and five of the new cases. The mutation was detected within the paternally expressed XL?s transcript in five and the maternally expressed NESP55 transcript in four cases. Tissues carrying paternal mutations appeared to have higher XL?s mRNA levels than maternal mutations. The human XL?s mutant analogous to Gs?-R201H (XL?s-R543H) showed markedly higher basal cAMP accumulation than wild-type XL?s in transfected cells. Wild-type XL?s demonstrated higher basal and isoproterenol-induced cAMP signaling than Gs? and co-purified with G?1?2 in transduced cells. XL?s mRNA was measurable in mouse calvarial cells, with its level being significantly higher in undifferentiated cells than those expressing preosteoblastic markers osterix and alkaline phosphatase. XL?s mRNA was also expressed in murine bone marrow stromal cells and preosteoblastic MC3T3-E1 cells. Our findings are consistent with the possibility that constitutive XL?s activity adds to the molecular pathogenesis of MAS and fibrous dysplasia of bone.

    View details for DOI 10.1016/j.bone.2010.09.032

    View details for Web of Science ID 000286543700019

    View details for PubMedID 20887824

  • Spermatogenesis and the regulation of Ca2+-calmodulin-dependent protein kinase IV localization are not dependent on calspermin MOLECULAR AND CELLULAR BIOLOGY Wu, J. Y., Ribar, T. J., Means, A. R. 2001; 21 (17): 6066-6070

    Abstract

    Calspermin and Ca(2+)-calmodulin-dependent protein kinase IV (CaMKIV) are two proteins encoded by the Camk4 gene. CaMKIV is found in multiple tissues, including brain, thymus, and testis, while calspermin is restricted to the testis. In the mouse testis, both proteins are expressed within elongating spermatids. We have recently shown that deletion of CaMKIV has no effect on calspermin expression but does impair spermiogenesis by disrupting the exchange of sperm basic nuclear proteins. The function of calspermin within the testis is unclear, although it has been speculated to play a role in binding and sequestering calmodulin during the development of the germ cell. To investigate the contribution of calspermin to spermatogenesis, we have used Cre/lox technology to specifically delete calspermin, while leaving kinase expression intact. We unexpectedly found that calspermin is not required for male fertility. We further demonstrate that CaMKIV expression and localization are unaffected by the absence of calspermin and that calspermin does not colocalize to the nuclear matrix with CaMKIV.

    View details for Web of Science ID 000170349900034

    View details for PubMedID 11486043

  • Female fertility is reduced in mice lacking Ca2+ calmodulin-dependent protein kinase IV ENDOCRINOLOGY Wu, J. Y., Gonzalez-Robayna, I. J., Richards, J. S., Means, A. R. 2000; 141 (12): 4777-4783

    Abstract

    Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) is a serine/threonine protein kinase with limited tissue distribution. CaMKIV is highly expressed in the testis, where it is found in transcriptionally inactive elongating spermatids. We have recently generated mice deficient in CaMKIV. In the absence of CaMKIV, the exchange of sperm nuclear basic proteins in male spermatids is impaired, resulting in male infertility secondary to defective spermiogenesis. The involvement of CaMKIV in female fertility has not been addressed. Here we report that female fertility is markedly reduced in CaMKIV-deficient mice due to impaired follicular development and ovulation. CaMKIV is expressed in the ovary, where it is localized in granulosa cells. We further find that in cultured granulosa cells, CaMKIV expression and subcellular localization are hormonally regulated. As granulosa cells differentiate, CaMKIV levels decrease and the kinase translocates from the nucleus into the cytoplasm. Our results demonstrate a critical role for CaMKIV in female reproduction and point to a potential function in granulosa cell differentiation.

    View details for Web of Science ID 000165360900056

    View details for PubMedID 11108293

  • Spermiogenesis and exchange of basic nuclear proteins are impaired in male germ cells lacking Camk4 NATURE GENETICS Wu, J. Y., Ribar, T. J., Cummings, D. E., Burton, K. A., McKnight, G. S., Means, A. R. 2000; 25 (4): 448-452

    Abstract

    Ca2+/calmodulin-dependent protein kinase IV (Camk4; also known as CaMKIV), a multifunctional serine/threonine protein kinase with limited tissue distribution, has been implicated in transcriptional regulation in lymphocytes, neurons and male germ cells. In the mouse testis, however, Camk4 is expressed in spermatids and associated with chromatin and nuclear matrix. Elongating spermatids are not transcriptionally active, raising the possibility that Camk4 has a novel function in male germ cells. To investigate the role of Camk4 in spermatogenesis, we have generated mice with a targeted deletion of the gene Camk4. Male Camk4-/- mice are infertile with impairment of spermiogenesis in late elongating spermatids. The sequential deposition of sperm basic nuclear proteins on chromatin is disrupted, with a specific loss of protamine-2 and prolonged retention of transition protein-2 (Tnp2) in step-15 spermatids. Protamine-2 is phosphorylated by Camk4 in vitro, implicating a connection between Camk4 signalling and the exchange of basic nuclear proteins in mammalian male germ cells. Defects in protamine-2 have been identified in sperm of infertile men, suggesting that our results may have clinical implications for the understanding of human male infertility.

    View details for Web of Science ID 000088615000024

    View details for PubMedID 10932193

  • Ca2+/calmodulin-dependent protein kinase IV is expressed in spermatids and targeted to chromatin and the nuclear matrix JOURNAL OF BIOLOGICAL CHEMISTRY Wu, J. Y., Means, A. R. 2000; 275 (11): 7994-7999

    Abstract

    Ca(2+)/calmodulin-dependent protein kinase IV and calspermin are two proteins encoded by the Camk4 gene. Both are highly expressed in the testis, where in situ hybridization studies in rat testes have demonstrated that CaMKIV mRNA is localized to pachytene spermatocytes, while calspermin mRNA is restricted to spermatids. We have examined the expression patterns of both CaMKIV and calspermin in mouse testis and unexpectedly find that CaMKIV is expressed in spermatogonia and spermatids but excluded from spermatocytes, while calspermin is found only in spermatids. CaMKIV and calspermin expression in the testis are stage-dependent and appear to be coordinately regulated. In germ cells, we find that CaMKIV is associated with the chromatin. We further demonstrate that a fraction of CaMKIV in spermatids is hyperphosphorylated and specifically localized to the nuclear matrix. These novel findings may implicate CaMKIV in chromatin remodeling during nuclear condensation of spermatids.

    View details for Web of Science ID 000085913300078

    View details for PubMedID 10713118

Books and Book Chapters


  • Development of the skeleton Osteoporosis, 4th Edition Provot, S., Schipani, E., Wu, J. Y., Kronenberg, H. M. Academic Press. 2013
  • The role of bone cells in establishing the hematopoietic stem cell niche Osteoimmunology: Interactions of the Immune and Skeletal Systems Wu, J. Y., Kronenberg, H. M. 2011: 81-99

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