Professor Tim Skerry
BVet.Med, FRCVS, Cert.SAO, PhD
Clinical Medicine, School of Medicine and Population Health
Professor of Orthopaedic Biology


+44 114 215 9026
Full contact details
Clinical Medicine, School of Medicine and Population Health
FU19, F Floor
The Medical School
Beech Hill Road
Sheffield
S10 2RX
- Profile
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For enquiries, please contact - iicd-om-operational@sheffield.ac.uk
- 2005 – Present: Professor of Orthopaedic Biology University of Sheffield; (Head of Department 2011-17).
- 2003 - 2005: Vice Principal Research RVC;
- 2001 – 2003: Head of Veterinary Basic Sciences; RVC
- 1995 – 2001: Professor of Cellular and Molecular Biology University of York;
- 1987 – 1995: Lecturer in Surgery, then Anatomy University of Bristol;
- 1984 – 1987: PhD Functional adaptation in bone;
- 1980 – 1986: Mixed practice, small animal practice, specialist orthopaedic practice;
- 1980: Veterinary Graduate RVC London.
- Research interests
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After spending a considerable number of years researching the mechanisms behind the way that the skeleton responds to exercise, my interests have shifted substantially in recent years. Interest in the calcitonin family of hormones and receptors led to a project on understanding the roles of so-called receptor activity modifying proteins in bone (RAMPs). RAMPs are interesting accessory proteins that control the ligand selectivity of a small number of receptors. For example a calcitonin receptor (CTR) alone binds and responds primarily to the hormone calcitonin.
However, co-expression of the CTR with any of the 3 human RAMPs leads to the heteromeric receptor complex becoming a one of 3 distinct receptors for the hormone amylin. Similarly, the calcitonin like-receptor (CLR) which is an orphan becomes a CGRP receptor with RAMP1 and either an adrenomedullin 1 or 2 receptor with RAMPs 2 and 3 respectively.
We have studied the roles of the RAMPs in bone by assessing the skeletal phenotypes of RAMP KO mice and shown that there appears to be no overt phenotype in RAMP 1 KO mice, there is a haploid insufficiency phenotype in RAMP2 heterozygotes with delayed development and intracortical porosity. In RAMP3 mice though there is accelerated development and an increased response of the bones to mechanical loading.
Our work on RAMPs has taken us into other directions too. Exploration of the role of RAMPs with other receptors where there is no change in ligand selectivity but a role in trafficking the receptors to the cell surface resulted in a paper on the need for RAMP1 for trafficking of the calcium sensing-receptor in a cell line not engineered to overexpress the proteins.
However, the main focus of the lab is now on development of small molecule antagonists of the AM2 adrenomedullin receptor. AM is involved centrally in regulation of blood pressure but it is also a potent player in tumorigenesis, where it has innate tumour cell to tumour cell actions, and roles in which AM released by the tumour upregulates AM2R expression in host cells around the tumour.
As a broad spectrum AM antagonist would interfere with AM’s potent vasodilator effect, we cannot tractably use such an approach to block AM’s role in tumours. However, we have shown that the physiological roles of AM are maintained predominantly by the AM1 receptor (CLR+RAMP2) while the AM2 receptor (CLR+RAMP3) can be blocked without significant deleterious effects.
Our major research programme is now a Wellcome Trust funded drug discovery programme in which Dr Gareth Richards and I work with collaborators in Industry (Dr Karl Gibson, a modeller at Sandexis and Dr Matt Tozer formerly a medicinal chemist at Peakdale Molecular) and Professor Joe Harrity in the Department of Chemistry here in Sheffield to develop and optimise small molecule AM2R antagonists for cancer treatment.
The success of the Wellcome funded programme has led to the identification of a candidate AM receptor antagonist molecule (and backup) suitable for development in oncology applications. Tim, Dr Gareth Richards and Professor Joe Harrity have formed a spinout company Modulus Oncology with the University, the Wellcome Trust and specialist Oncology incubator specialists Cumulus Oncology to progress development.
Developments of the Wellcome research programme have led to pilot data that provided proof of concept for the development of small molecule antagonists of the AM1 adrenomedullin receptor, and at reversing the catastrophic low blood pressure in septic shock. This has led to support from the Rosetrees Trust (£250,000), an EPSRC studentship and a European Lead Factory collaboration to screen huge compound libraries for novel AM1 binding molecules.
- Publications
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Show: Featured publications All publications
Featured publications
Journal articles
- Cross-species RNA-seq study comparing transcriptomes of enriched osteocyte populations in the tibia and skull. Frontiers in Endocrinology, 11. View this article in WRRO
- Discovery of a First-in-Class Potent Small Molecule Antagonist against the Adrenomedullin-2 Receptor. ACS Pharmacology & Translational Science, 3(4), 706-719. View this article in WRRO
- Peak strain magnitudes and rates in the tibia exceed greatly those in the skull: An in vivo study in a human subject. Journal of Biomechanics, 48(12), 3292-3298. View this article in WRRO
- Role of receptor activity modifying protein 1 in function of the calcium sensing receptor in the human TT thyroid carcinoma cell line.. PLoS One, 9(1), e85237. View this article in WRRO
- Research resource: Haploinsufficiency of receptor activity-modifying protein-2 (RAMP2) causes reduced fertility, hyperprolactinemia, skeletal abnormalities, and endocrine dysfunction in mice.. Mol Endocrinol, 25(7), 1244-1253.
- Absence of mechanical loading in utero influences bone mass and architecture but not innervation in Myod-Myf5-deficient mice. J Anat, 210(3), 259-271.
- Evidence for a novel glutamate-mediated signaling pathway in keratinocytes. The Journal of investigative dermatology, 112(3), 337-342.
- The glutamate receptor antagonist MK801 modulates bone resorption in vitro by a mechanism predominantly involving osteoclast differentiation.. FASEB J, 13(15), 2179-2185.
- PTH/PTHrP receptor expression on osteoblasts and osteocytes but not resorbing bone surfaces in growing rats. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 10(12), 1935-1943.
- Early strain-related changes in enzyme activity in osteocytes following bone loading in vivo. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 4(5), 783-788.
All publications
Books
- Novel Approaches to Treatment of Osteoporosis. Springer Berlin Heidelberg.
Journal articles
- Early life vitamin D depletion and mechanical loading determine methylation changes in the RUNX2, RXRA, and osterix promoters in mice. Genes & Nutrition, 17(1).
- Accelerated development with increased bone mass and skeletal response to loading suggest receptor activity modifying protein-3 as a bone anabolic target. Frontiers in Endocrinology, 12. View this article in WRRO
- Feeding intervention potentiates the effect of mechanical loading to induce new bone formation in mice. The FASEB Journal, 35(10).
- Analysis of mechanotransduction dynamics during combined mechanical stimulation and modulation of the extracellular-regulated kinase cascade uncovers hidden information within the signalling noise. Interface Focus, 11(1).
- Cross-species RNA-seq study comparing transcriptomes of enriched osteocyte populations in the tibia and skull. Frontiers in Endocrinology, 11. View this article in WRRO
- Discovery of a First-in-Class Potent Small Molecule Antagonist against the Adrenomedullin-2 Receptor. ACS Pharmacology & Translational Science, 3(4), 706-719. View this article in WRRO
- Revealing hidden information in osteoblast’s mechanotransduction through analysis of time patterns of critical events. BMC Bioinformatics, 21(1). View this article in WRRO
- Heterogeneity in the mechanical properties of integrins determines mechanotransduction dynamics in bone osteoblasts. Scientific Reports, 9(1). View this article in WRRO
- Analysis of RAMP3 gene polymorphism with body composition and bone density in young and elderly women. Gene, 721(Supplement). View this article in WRRO
- Early life vitamin D depletion alters the postnatal response to skeletal loading in growing and mature bone.. PLoS ONE, 13(1). View this article in WRRO
- Compound heterozygous variants in NBAS as a cause of atypical osteogenesis imperfecta.. BONE, 94, 65-74. View this article in WRRO
- Peak strain magnitudes and rates in the tibia exceed greatly those in the skull: An in vivo study in a human subject. Journal of Biomechanics, 48(12), 3292-3298. View this article in WRRO
- Modulation of Glucagon Receptor Pharmacology by Receptor Activity-modifying Protein-2 (RAMP2). Journal of Biological Chemistry, 290(38), 23009-23022. View this article in WRRO
- Inhibition of glutamate regulated calcium entry into leukemic megakaryoblasts reduces cell proliferation and supports differentiation. Cellular Signalling, 27(9), 1860-1872. View this article in WRRO
- Zinc‐Induced Effects on Osteoclastogenesis Involves Activation of Hyperpolarization‐Activated Cyclic Nucleotide Modulated Channels via Changes in Membrane Potential. Journal of Bone and Mineral Research, 30(9), 1618-1626.
- Maternal vitamin D deficiency alters later skeletal responsiveness to mechanical loading in a model system. Bone Abstracts.
- Maternal vitamin D depletion disrupts neonatal skeletal development in mice. Bone Abstracts.
- Role of receptor activity modifying protein 1 in function of the calcium sensing receptor in the human TT thyroid carcinoma cell line.. PLoS One, 9(1), e85237. View this article in WRRO
- Correction for Whitehouse et al., Neighbor of Brca1 gene (Nbr1) functions as a negative regulator of postnatal osteoblastic bone formation and p38 MAPK activity. Proceedings of the National Academy of Sciences, 110(11), 4428-4428.
- The P2Y13 receptor regulates extracellular ATP metabolism and the osteogenic response to mechanical loading.. J Bone Miner Res, 28(6), 1446-1456. View this article in WRRO
- Reduced bone turnover in mice lacking the P2Y13 receptor of ADP.. Mol Endocrinol, 26(1), 142-152. View this article in WRRO
- Research resource: Haploinsufficiency of receptor activity-modifying protein-2 (RAMP2) causes reduced fertility, hyperprolactinemia, skeletal abnormalities, and endocrine dysfunction in mice.. Mol Endocrinol, 25(7), 1244-1253.
- Analysis of mouse models with loss or mutations in Nbr1 demonstrate an age-dependent high bone mass due to altered osteoblast activity. Bone, 47, S43-S43.
- Neighbor of Brca1 gene (Nbr1) functions as a negative regulator of postnatal osteoblastic bone formation and p38 MAPK activity.. Proc Natl Acad Sci U S A, 107(29), 12913-12918.
- Systemic and contralateral responses to loading of bones.. J Bone Miner Res, 24(4), 753.
- Ultrasound mimics the effect of mechanical loading on bone formation in vivo on rat ulnae. Med Eng Phys, 31(1), 42-47.
- Role of Nbr1 in bone remodeling. Bone, 44(2), S296-S296.
- The response of bone to mechanical loading and disuse: fundamental principles and influences on osteoblast/osteocyte homeostasis.. Arch Biochem Biophys, 473(2), 117-123.
- Absence of mechanical loading in utero influences bone mass and architecture but not innervation in Myod-Myf5-deficient mice. J Anat, 210(3), 259-271.
- Microarray analysis of healing rat Achilles tendon: evidence for glutamate signaling mechanisms and embryonic gene expression in healing tendon tissue. Journal of orthopaedic research : official publication of the Orthopaedic Research Society, 24(4), 842-855.
- Direct transformation from quiescence to bone formation in the adult periosteum following a single brief period of bone loading. (Reprinted from J Bone Miner Res, vol 3, pg 647-656, 1988). JOURNAL OF BONE AND MINERAL RESEARCH, 20(1), 161-171.
- Sympathetic nervous system does not mediate the load-induced cortical new bone formation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 20(12), 2159-2168.
- Characterization of acetylcholinesterase expression and secretion during osteoblast differentiation. Bone, 35(4), 819-827.
- Mechanical loading: biphasic osteocyte survival and targeting of osteoclasts for bone destruction in rat cortical bone.. Am J Physiol Cell Physiol, 284(4), C934-C943.
- Investigation of the regulation of bone mass by mechanical loading: from quantitative cytochemistry to gene array. Cell Biochem Funct, 21(3), 223-229.
- NMDA receptor-mediated regulation of human megakaryocytopoiesis. Blood, 102(4), 1254-1259.
- Osteoprotegerin inhibits the development of osteolytic bone disease in multiple myeloma.. Blood, 98(13), 3534-3540.
- Glutamate: A Potential Regulator of Keratinocyte Phenotype. Biochemical Society Transactions, 28(3), A82-A82.
- Glutamate signalling in bone: A therapeutic target for osteoporosis?. Expert Opinion on Therapeutic Targets, 4(2), 207-218.
- Non-neuronal glutamate signalling pathways. Expert Opinion on Therapeutic Targets, 4(3), 333-345.
- Tetracyclines induce apoptosis in osteoclasts.. Bone, 27(1), 75-80.
- Expression of a Functional N-Methyl-d-Aspartate–Type Glutamate Receptor by Bone Marrow Megakaryocytes. Blood, 93(9), 2876-2883.
- Effects of the NSAIDs meloxicam and indomethacin on cartilage proteoglycan synthesis and joint responses to calcium pyrophosphate crystals in dogs.. Vet Res Commun, 23(2), 101-113.
- Evidence for a novel glutamate-mediated signaling pathway in keratinocytes. The Journal of investigative dermatology, 112(3), 337-342.
- The glutamate receptor antagonist MK801 modulates bone resorption in vitro by a mechanism predominantly involving osteoclast differentiation.. FASEB J, 13(15), 2179-2185.
- O4. Comparison of physiological strains in the human skull and tibia. Bone, 19(6), 686-686.
- P52. Ovariectomy causes profound bone loss from the tibiae but not the calvariae of rats. Bone, 19(6), 699-699.
- EVIDENCE FOR THE EXPRESSION OF THE BCL-2 PROTO-ONCOGENE BY HUMAN CELLS OF THE OSTEOBLAST LINEAGE. Biochemical Society Transactions, 24(4), 603s-603s.
- Constitutive in vivo mRNA expression by osteocytes of beta-actin, osteocalcin, connexin-43, IGF-I, c-fos and c-jun, but not TNF-alpha nor tartrate-resistant acid phosphatase. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 11(3), 350-357.
- Thyroparathyroidectomy reduces ovariectomy-induced trabecular bone loss in the adult rat tibia. Bone, 17(6), 581-581.
- PTH receptor binding on osteocytes in cortical and trabecular bone. Bone, 17(6), 562-562.
- Expression of a glutamate/aspartate transporter (glast) in osteocytes. A role for excitatory amino acids as paracrine osteotropic agents?. Bone, 17(6), 568-568.
- View this article in WRRO
- Candidate genes in the osteocyte response to mechanical loading in vivo. Bone, 17(3), 319-319.
- Effects of elcatonin, etidronate and indomethacin on bone resorption rate in growing rats. Bone, 16(6), 685-685.
- PTH/PTHrP receptor mRNA expression on forming but not resorbing surfaces in growing rat ulnae. Bone, 16(6), 680-680.
- PTH/PTHrP receptor expression on osteoblasts and osteocytes but not resorbing bone surfaces in growing rats. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 10(12), 1935-1943.
- O9. Inhibition of osteoclastic resorption in vivo during the reversal phase of the bone remodelling cycle. Bone, 15(6), 731-731.
- P12. Formation and resorption in the modelling rat ulna. Bone, 15(4), 454-455.
- P13. Electrophysiological responses of cultured osteoblasts to PTH vitamin D and oestrogen. Bone, 15(4), 455-455.
- P24. Differences in gene expression in growing bone. Bone, 15(2), 235-236.
- CONSERVATIVE AND SURGICAL-TREATMENT OF CANINE ACETABULAR FRACTURES - A REVIEW OF 34 CASES. JOURNAL OF SMALL ANIMAL PRACTICE, 35(3), 139-143.
- Immobilization induced trabecular bone loss is not modulated by calcitonin treatment. Bone, 13(5), A31-A31.
- Ovariectomy reduces uptake of calcium in vivo by the tibia and vertebral body but not the calvaria. Bone and Mineral, 17, 164-164.
- P45. Short term disuse promotes skeletal uptake of calcium. Bone, 13(1), 118-118.
- Modulation of bone loss during disuse by pulsed electromagnetic fields. Journal of orthopaedic research : official publication of the Orthopaedic Research Society, 9(4), 600-608.
- P14. The effects of direct loading versus hydrostatic pressure on proteoglycan orientation in bone. Bone, 10(2), 151-151.
- Early strain-related changes in enzyme activity in osteocytes following bone loading in vivo. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 4(5), 783-788.
- EARLY CELLULAR-RESPONSES IN LOAD-RELATED ADAPTIVE BONE REMODELING. BONE, 9(4), 255-255.
- PROTEOGLYCAN REORIENTATION IN RESPONSE TO APPLIED BONE LOADING, A POSSIBLE SIGNAL FOR BONE REMODELING. BONE, 9(4), 264-264.
- Direct transformation from quiescence to bone formation in the adult periosteum following a single brief period of bone loading. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 3(6), 647-656.
- Targeting the adrenomedullin-2 receptor for the discovery and development of novel anti-cancer agents. Expert Opinion on Drug Discovery, 1-10.
- Discovery of a First-In-Class Small Molecule Antagonist against the Adrenomedullin-2 Receptor: Structure–Activity Relationships and Optimization. Journal of Medicinal Chemistry.
- Role of receptor activity modifying protein 3 in the response of bone to mechanical loading. Bone Abstracts.
- Role of receptor activity modifying proteins in skeletal regulation. Bone Abstracts.
- Accelerated skeletal development and high bone mass in mice lacking RAMP3. Frontiers in Endocrinology, 2.
- Expression of calcium sensing receptor and receptor activity modifying proteins in cells involved in calcium homeostasis and fluorescence resonance energy transfer based stoichiometric analysis of their interactions. Frontiers in Endocrinology, 2.
- Novel regulation steps in parathyroid receptor activation. Frontiers in Endocrinology, 2.
- Nitric oxide activates matrix metalloproteinases indirectly in human articular chondrocytes. International Journal of Experimental Pathology, 81(1), A17-A17.
Chapters
- Mechanosensing in Bone and the Role of Glutamate Signalling, Mechanosensing Biology (pp. 181-191). Springer Japan
- Bone Cells and Bone Remodelling in Rheumatoid Arthritis, Mechanisms and Models in Rheumatoid Arthritis (pp. 205-220). Elsevier
- Mechanical and hormonal influences in vivo cause regional differences in bone remodelling, Biomechanics and Cells (pp. 164-177).
- Skeletal strain and the maintenance of bone mass, Proceedings of the First International Conference on Interfaces in Medicine and Mechanics (pp. 167-172). Springer Netherlands
- Models for mechanical loading of hone and hone cells in vivo and in vitro, Methods in Bone Biology (pp. 149-176). Springer US
Conference proceedings papers
- NBAS variants causing a novel form of inherited bone fragility. Bone Abstracts, Vol. 6(2017). Bristol, UK, 10 June 2017 - 13 June 2017. View this article in WRRO
- Feeding after overnight fast enhances bone’s response to mechanical loading in mice. Journal of Bone and Mineral Research, Vol. 31(S1) (pp S403-S403). USA, 16 September 2016 - 19 September 2016. View this article in WRRO
- Microarray analysis of healing rat Achilles tendon: Evidence for glutamate signalling mechanisms and embryonic gene expression in healing tendon tissue. Journal of Orthopaedic Research
Patents
- View this article in WRRO
Preprints
- Feeding intervention potentiates the effect of mechanical loading to induce new bone formation in mice.
- Cross-species RNA-seq study comparing transcriptomes of enriched osteocyte populations in the tibia and skull. Frontiers in Endocrinology, 11. View this article in WRRO
- Research group
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Members of research group
- Dr Gareth Richards (Joint Group Leader)
- Dr Paris Avgoustou
- Dr Ameera Jailani
PhD students
- Jo Holmes
- Kamilla Bigos
- Ewan Lilley
- Robbie Hathaway (jointly with Prof Joe Harrity)
- Grants
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Principal funding sources
- Professional activities and memberships
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- CSO Modulus Oncology.