Benjamin Alman

Benjamin Alman MD, FRCPC
Professor
Department of Surgery
Benjamin Alman
Contact Info
T: (416) 813-2178
F: (416) 813-5252
Website
Location
Hospital for Sick Children (SickKids)
686 Bay St. Ste. 16-9-702
Toronto, ON, M5G 0A4
Appointment Status Cross-Appointed
Research Interests
Molecular & Cell Biology, Cancer

Dr. Alman is an orthopaedic clinician-scientist, whose research focuses on understanding role of developmentally important processes in pathologic and reparative process involving the musculoskeletal system. 

The long-term goal of his work is to use this knowledge to identify improved therapeutic approaches to orthopaedic disorders. 

He makes extensive use of genetically modified mice to model human disease, and has used this approach to identify new drug therapies for musculoskeletal tumors and to improve the repair process in cartilage, skin, and bone.  He also works on cellular heterogeneity in sarcomas, and has identified a subpopulation of tumor initiating cells in musculoskeletal tumors. In this work, he also has identified specific cell populations that are responsible for joint and bone development. 

Dr Alman studies how processes important in normal development are recapitulated in repair processes or dysregulated in pathologic processes involving the musculoskeletal system. The Alman lab is unraveling the role of signaling pathways such as Wnt and hedgehog, in stem cells, during embryonic development, in tissue repair and regeneration, as well as in neoplasia.

Research/Teaching

Research Synopsis

Research in The Alman lab focusses on five broad areas:

  1. Wound Healing
  2. Stem Cells and Neoplasia
  3. Cartilage and Joint Development
  4. Joint Degeneration and Repair
  5. Bone Regeneration.

Wound healing

The entire wound healing process is a complex series of events that begins at the moment of injury and can continue for months to years.

Our goal is to determine the role of the Wnt pathway, particularly its key molecule β-catenin, in the reconstitution of epithelial and dermal components of the skin during wound healing.

Using different genetically engineered mice designed in our lab, we investigate the fate of the cells that contribute to healing and the role of β-catenin in this process.

As part of this work, we identified a novel drug that can be used to decrease scar size, and are working to determine how it can be developed into a topical agent to use for patients.

Stem Cells and Neoplasia

Stem cells are the earliest step in the hierarchal progressive maturation to functionally differentiated cells with characteristics of self-renew and fast proliferation.

Although the concept that tumours contain a subpopulation of cells with stem cell properties has been demonstrated in a number of tumour types, little has been reported on the role of stem cells in musculoskeletal (MSK) tumours, perhaps due to lack of unique mesenchymal stem cell (MSC) marker.

In our studies, we hypothesize that MSK tumours contain a subpopulation of tumour initiating cells.

The first step in our research is to identify and isolate tumour initiating cells (TIC) from musculoskeletal tumours. Further study of this population of cells will allow for the characterization of molecular pathways regulating the development of MSK, ultimately identifying potential novel therapeutic targets.

We are also studying the role of developmentally important signalling pathways in fibrous and cartilaginous tumours.

In this work, we generated genetically modified mice that developed these tumours, and are studying how modulating the signalling pathways causes these tumours, and how this information could be used to develop potential new therapeutic approaches.

Cartilage and joint development

During development, cell fate experiments have determined that growth plate and articular chondrocytes differentiate from two distinct populations of cells.

Within the growth plate, Indian hedgehog (Ihh) regulates chondrocyte proliferation and differentiation that involves a feedback loop with the parathyroid hormone related protein (PTHrP).

We have generated transgenic mice showing that a deregulation of the hedgehog/PTHrP feedback loop during growth plate development that results in chondrodysplasias and the development of cartilage tumours; however, the role of hedgehog signalling in the differentiation and maintenance of articular chondrocyte progenitors is poorly defined.

Through investigation of transgenic mice, we hope to further identify the role of hedgehog, and other signalling pathways, on growth plate and articular cartilage development.

Joint degeneration and repair

Osteoarthritis (OA) is a degenerative disease of the joints, characterized by degradation and calcification of articular cartilage, and subchondral bone changes.

Because articular cartilage does not regenerate, understanding how joints develop may provide new insight and novel therapies for OA. Our current data suggests that Wnt, Hh, sterols and other signaling pathways involved in normal joint development may also be involved in the development and progression of OA.

Therefore, we aim to elucidate how modulating these pathways can attenuate OA pathology and enhance joint repair.

Bone regeneration

Endochondral ossification is recapitulated during long-bone repair. Although the β-catenin pathway has been investigated in the context of bone development and skeletogenesis, its role in the bone regeneration processes is not clear.

Using pharmalogical reagents, we are able to augment β-catenin signaling during bone repair and have observed substantially improved healing in various pathological conditions.

Deficiencies seen in bone regeneration with age are (in part) mediated by the β-catenin pathway. Our models which are able to “rejuvenate” aged bone regeneration do so in a β-catenin dependent manner.

Mutation in the FGFR3 gene (achondroplasia) results in augmented bone repair and cellular differentiation.

We are currently investigating the impact of FGFR3 signalling on osteoblast differentiation.

Furthermore, we are also investigating how glucocorticoids induce osteoporosis in chronic paediatric diseases such as Acute Lymphoblastic Leukemia and Duchene Muscular Dystrophy.

Insights into these pathways and diseases may offer new therapeutic options with which to enhance bone regeneration or fracture repair.    

Publications and Awards

View PubMed search of this faculty member's recent publications.

Recent Publications

Bielefeld KA, Amini-Nik S, Whetstone H, Poon R, Youn A, Wang J, Alman BA. Fibronectin and beta-catenin act in a regulatory loop in dermal fibroblasts to modulate cutaneous healing. Journal of Biological Chemistry. 2011: 286(31): 27687-27697.

Hsu SC, Zhang X, Yu C, Li ZJ, Wunder JS, Hui CC, Alman BA. Kif7 promotes Hedgehog signaling in growth plate chondrocytes by restricting the inhibitory function of Sufu. Development. 2011: 138(17): 3791-3801.

Amini-Nik S, Glancy D, Boimer C, Whetstone H, Keller C, Alman BA. Pax7 expressing cells contribute to dermal wound repair regulating scar size through a beta-catenin mediated process. Stem Cells. 2011: 29(9): 1371-1379.

Wang CY, Wei Q, Han I, Sato S, Ghanbari-Azarnier R, Whetstone H, Poon R, Hu J, Zheng F, Zhang P, Wang W, Wunder JS, Alman BA. Hedgehog and notch signaling regulate self-renewal of undifferentiated pleomorphic sarcoma. Cancer Research. 2012: 72(4): 1013-1022.

Poon R, Hong H, Wei X, Pan J, Alman BA. A high throughput screen identifies Nefopam as targeting cell proliferation in β-catenin driven neoplastic and reactive fibroproliferative disorders. PLoS ONE. 2012: 7(5): e37940.

Hsu C, Zhang X, Cheng S, Wunder JS, Hui CC, Alman BA. Suppressor of fused (Sufu) mediates the effect of Parathyroid hormone-like hormone (Pthlh) on chondrocyte differentiation in the growth plate. Journal of Biological Chemistry. 2012: 287(43): 36222-36228.

Ho L, Ali SA, Al-Jazrawe M, Kandel R, Wunder JS, Alman BA. Primary cilia attenuate Hedgehog signalling in neoplastic chondrocytes.  Oncogene. 2013: 32(47):5388-5396.

Ghanbari-Azarnier R, Sato S, Wei Q, Al-Jazrawe M, Alman BA.  Targeting stem cell behavior in desmoid tumors (aggressive fibromatosis) by inhibiting hedgehog signaling.  Neoplasia. 2013 Jul;15(7):712-719.

Baht GS, Silkstone D, Nadesan P, Whetstone H, Alman BA.  Activation of hedgehog signaling during fracture repair enhances osteoblastic-dependent matric formation.  J Orthop Res.  2014 Apr;32(4): 581-586.

Amini-Nik S, Cambridge E, Yu W, Guo A, Whetstone H, Nadesan P, Poon R, Hinz B, Alman BA.  β-Catenin-regulated myeloid cell adhesion and migration determine wound healing.  J Clin Invest. 2014 Jun 2;124(6):2599-2610.

Hirata M, Sasaki M, Cairns RA, Inoue S, Puviindran V, Li WY, Snow BE, Jones LD, Wei Q, Sato S, Tang YJ, Nadesan P, Rockel J, Whetstone H, Poon R, Weng A, Gross S, Straley K, Gliser C, Xu Y, Wunder J, Mak TW, Alman BA.  Mutant IDH is sufficient to initiate enchondromatosis in mice.  Proc Natl Acad Sci U S A. 2015 Mar 3;112(9):2829-2834.

Baht GS, Silkstone D, Vi L, Nadesan P, Amani Y, Whetstone H, Wei Q, Alman BA.  Exposure to a youthful circulaton rejuvenates bone repair through modulation of β-catenin.  Nat Commun. 2015 May 19;6:7131.

Alman BA.  The role of hedgehog signaling in skeletal health and disease.  Nature Reviews.  Rheumatology. 2015; 11(9):552-560.

Vi L, Baht GS, Whetstone H, Ng A, Wei Q, Poon R, Mylvaganam S, Grynpas M, Alman BA. Macrophages promote osteoblastic differentiation in-vivo: implications in fracture repair and bone homeostasis. J Bone Miner Res. 2015 Jun;30(6):1090-1102.

Ali SA, Al-Jazrawe M, Ma H, Whetstone H, Poon R, Farr S, Naples M, Adeli K, Alman B.  Regulation of Cholesterol Homeostasis by Hedgehog Signaling in Osteoarthritic Cartilage.  Arthritis & Rheumatology.  2016; 68(1):127-137.