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Laboratory of Skeletal Stem Cells

Matthew B. Greenblatt, MD, PhD, Principal Investigator

Approximately half of all women and a fifth of all men will experience a skeletal fracture due to osteoporosis or other diseases causing low bone mass. These fractures kill as many women each year as breast cancer, as fractures often lead to immobility that in turn leads a spiral of progressive deconditioning that can ultimately prove fatal. Improving clinical outcomes in this area will ultimately require finding new therapeutic agents that promote the generation or activity of osteoblasts, the cells that build bone. Ultimately, all bone-forming osteoblasts come from skeletal stem cells, an adult stem cell type that has only recently begun to be studied. A key focus of our work has been the idea that there is not a single skeletal stem cell, but many versions of these cells, each residing in different regions of the skeleton and having distinct contributions to both the normal formation of the skeleton and to the development of skeletal diseases. Our work in this area started with the identification of a new stem cell on the outer surface of bone (Debnath et al., Nature 2018) and is now continuing to identify new stem cells in other regions of the skeleton, including the spine and the skull.

We are also investigating the environmental factors and signals that both support these stem cells and drive their production of bone-forming osteoblasts. In our prior work, we have identified that osteoblasts secrete factors known as SLITs that promote the formation of special blood vessels that in turn tailor the environment in bone to favor new bone formation (Xu et al., Nature Medicine 2018). Accordingly, treatment with SLITs can promote new skeletal blood vessel formation and also reverse bone loss in mouse models of osteoporosis or promote healing in models of fracture repair. In other studies, we have identified a new therapeutic target for the treatment of neurofibromatosis type 1, a disorder whose manifestations include skeletal fragility and impaired fracture healing (Bok et al., Nature Communications 2020). Lastly, we have also identified a new receptor on osteoblasts that regulates responses to a family of proteins, termed the hedgehog family, that provide environmental signals controlling bone formation (Sun et al., Nature Communications 2021). Currently, we are both working to explore how these discoveries may be relevant for the treatment of skeletal disorders and also to identify new therapeutic approaches to increase bone mass and prevent fractures, both in osteoporosis and also in rare genetic diseases of bone.

Active Projects:

Currently, an area of focus in the lab is understanding how alterations in the signaling of mitogen activated protein kinases contribute to the development of both osteoporosis and rare skeletal disorders, with a particular emphasis on discovering approaches to target these pathways for therapeutic benefit in humans.

Active Grants:

  • Novartis BioPharma Alliance Agreemeent
    PI: Matthew Greenblatt, MD, PhD
    Novartis Insitutes for BioMedical Research
  • Stem cell basis for bone microarchitecture, materials properties, and anabolic responses to loading
    PI: Matthew Greenblatt, MD, PhD
    Weill Cornell Medical College
  • Establishing Pathways for Endothelial Support of Bone Formation with SLIT3
    PI: Matthew Greenblatt, MD, PhD
    National Institute of Arthritis & Musculoskeletal & Skin Diseases
  • Biology of cortical bone of long bones and calvarium: Role of Sfrp4 in periosteal bone formation
    PI Subaward: Matthew Greenblatt, MD, PhD
    National Institute of Dental & Craniofacial Research
  • Tumor-Selective Delivery Approaches for Medulloblastoma
    PI Subaward: Matthew Greenblatt, MD, PhD
    National Cancer Institute
  • Targeting Skeletal Stem Cells to Treat Tumor-induced Osteolysis
    PI: Matthew Greenblatt, MD, PhD
    The Pershing Square Sohn Cancer Research Alliance
  • Investigation of the Roles for CaV1.2 in Non-Excitable Tissue During Development
    Co-Investigator: Matthew Greenblatt, MD, PhD
    National Institute of Child Health & Human Development
  • Novel Mechanisms of Bone Formation
    PI: Matthew Greenblatt, MD, PhD
    Burroughs Wellcome Fund Career Award for Medical Scientists

Selected Publications

Discovery of a periosteal stem cell mediating intramembranous bone formation

Matthew B. Greenblatt, MD, PhD

Discovery of a periosteal stem cell mediating intramembranous bone formation

Nature. 2018 Oct;562(7725):133-139. 

Debnath S, Yallowitz AR, McCormick J, Lalani S, Zhang T, Xu R, Li N, Liu Y, Yang YS, Eiseman M, Shim JH, Hameed M, Healey JH, Bostrom MP, Landau DA, Greenblatt MB.

PMID: 30250253; PMCID: PMC6193396

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SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts

Matthew B. Greenblatt, MD, PhD

SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts

Nat Commun. 2021 Jul 29;12(1):4611. 

Sun J, Shin DY, Eiseman M, Yallowitz AR, Li N, Lalani S, Li Z, Cung M, Bok S, Debnath S, Marquez SJ, White TE, Khan AG, Lorenz IC, Shim JH, Lee FS, Xu R, Greenblatt MB.

PMID: 34326333; PMCID: PMC8322311

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MEKK2 mediates aberrant ERK activation in neurofibromatosis type I

Matthew B. Greenblatt, MD, PhD

MEKK2 mediates aberrant ERK activation in neurofibromatosis type I

Nat Commun. 2020 Nov 11;11(1):5704.

Bok S, Shin DY, Yallowitz AR, Eiseman M, Cung M, Xu R, Li N, Sun J, Williams AL, Scott JE, Su B, Shim JH, Greenblatt MB.

PMID: 33177525; PMCID: PMC7658220.

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Targeting skeletal endothelium to ameliorate bone loss

Matthew B. Greenblatt, MD, PhD

Targeting skeletal endothelium to ameliorate bone loss

Nat Med. 2018 Jun;24(6):823-833. 

Xu R, Yallowitz A, Qin A, Wu Z, Shin DY, Kim JM, Debnath S, Ji G, Bostrom MP, Yang X, Zhang C, Dong H, Kermani P, Lalani S, Li N, Liu Y, Poulos MG, Wach A, Zhang Y, Inoue K, Di Lorenzo A, Zhao B, Butler JM, Shim JH, Glimcher LH, Greenblatt MB.

PMID: 29785024; PMCID: PMC5992080

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