Development of Novel Models for Studying Osteoclasts
Author
Summary, in English
This thesis focuses on developing and characterizing novel models for studying osteoclasts with an emphasis on how mutations abolishing osteoclastic acidification affect osteoclast signaling and bone remodeling, as well as how to treat patients bearing these rare mutations.
Bone remodeling is under normal circumstances a tightly balanced process where resorption of bone by osteoclasts is followed by adequate amounts of bone formation by osteoblasts.Mutations in the TCIRG1 gene lead to severe autosomal recessive osteopetrosis (ARO) in both mice and man, characterized by lack of bone resorption as a result of abolished acid secretion, an increased number of non-resorbing osteoclasts, but normal or even increased bone formation.
The first two papers are based on studies in adult mice transplanted with stem cells from either osteoclast-rich osteopetrotic mice (oc/oc) or osteoclast-poor osteopetrotic mice (RANK KO). The first paper focuses on characterizing the bone and cellular phenotype in the adult osteopetrotic mouse model and find that bones, are both bigger and, in contrast to the endogenous oc/oc mouse model, stronger in mice transplanted with osteopetrotic stem cells compared to wild type transplanted mice. In the second paper we compare the osteoclast-rich osteopetrotic oc/oc transplanted model to adult mice transplanted with stem cells from the osteoclast-poor RANK KO mouse, and find that maintaining non-resorbing osteoclasts in vivo increases bone formation. In the third paper we investigate the role of bone matrix, cell stage and resorptive function on osteoclast mediated anabolic signaling. In paper IV human stem cells from patients with ARO were investigated and we provide the first proof-of-principle for lentiviral mediated correction of resorptive function in CD34+ derived osteoclasts from ARO patients.
The results can be devided into two exciting branges. Data obtained in the adult osteopetrotic mouse models encourage further development of molecules targeting the acidification process in osteoclasts when treating low bone mineral density diseases. Furthermore, the correctional results in the ARO patient cells are very promising, and will serve as basis for further development of clinical gene therapy of osteopetrosis.
Bone remodeling is under normal circumstances a tightly balanced process where resorption of bone by osteoclasts is followed by adequate amounts of bone formation by osteoblasts.Mutations in the TCIRG1 gene lead to severe autosomal recessive osteopetrosis (ARO) in both mice and man, characterized by lack of bone resorption as a result of abolished acid secretion, an increased number of non-resorbing osteoclasts, but normal or even increased bone formation.
The first two papers are based on studies in adult mice transplanted with stem cells from either osteoclast-rich osteopetrotic mice (oc/oc) or osteoclast-poor osteopetrotic mice (RANK KO). The first paper focuses on characterizing the bone and cellular phenotype in the adult osteopetrotic mouse model and find that bones, are both bigger and, in contrast to the endogenous oc/oc mouse model, stronger in mice transplanted with osteopetrotic stem cells compared to wild type transplanted mice. In the second paper we compare the osteoclast-rich osteopetrotic oc/oc transplanted model to adult mice transplanted with stem cells from the osteoclast-poor RANK KO mouse, and find that maintaining non-resorbing osteoclasts in vivo increases bone formation. In the third paper we investigate the role of bone matrix, cell stage and resorptive function on osteoclast mediated anabolic signaling. In paper IV human stem cells from patients with ARO were investigated and we provide the first proof-of-principle for lentiviral mediated correction of resorptive function in CD34+ derived osteoclasts from ARO patients.
The results can be devided into two exciting branges. Data obtained in the adult osteopetrotic mouse models encourage further development of molecules targeting the acidification process in osteoclasts when treating low bone mineral density diseases. Furthermore, the correctional results in the ARO patient cells are very promising, and will serve as basis for further development of clinical gene therapy of osteopetrosis.
Department/s
Publishing year
2014
Language
English
Publication/Series
Lund University Faculty of Medicine Doctoral Dissertation Series
Volume
2014:111
Document type
Dissertation
Publisher
Division of Molecular Medicine and Gene Therapy
Topic
- Hematology
Keywords
- Osteoclast
- Osteopetrosis
- Osteoporosis
- Bone
- Hematopoiesis
- Gene Therapy
- Mouse Models
- oc/oc
- RANK KO
Status
Published
Supervisor
- Johan Richter
- Kim Henriksen
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-7619-040-1
Defence date
10 October 2014
Defence time
13:00
Defence place
Segerfalk lecture hall, BMC A10 Sölvegatan 17, Lund
Opponent
- Ulf Lerner