Phenotypes Associated with This Genotype

Genotype
MGI:5693162

• Allelic Composition: Bmp1^tm1.1Dgr/Bmp1^tm1.1Dgr; Tll1^tm2.1Dgr/Tll1^tm2.1Dgr; Ndor1^{Tg(UBC-cre/ERT2)1Ejb}/0
• Genetic Background: involves: 129S/SvEv * 129S6/SvEvTac * C57BL/6 * SJL

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

growth/size/body

decreased body size ( J:210366 )

• at 17 weeks of age, postnatally tamoxifen-treated mice are runted relative to control littermates

slow postnatal weight gain ( J:210366 )

• tamoxifen-treated mice exhibit reduced weight gain, so that by 17 weeks of age (11 weeks after the final tamoxifen injection), they are significantly smaller, with an average weight 73% of controls

• difference in weight is partly due to a reduction in adipose tissue

decreased body length ( J:210366 )

• at 17 weeks of age, tamoxifen-treated mice show a 13% reduction in total body length (nose to anus)

skeleton

increased osteoclast cell number ( J:210366 )

• TRAP staining revealed a sharp increase in numbers of osteoclasts lining bone surfaces in both trabecular and cortical bone of femurs in tamoxifen-treated mice relative to controls

• osteoclasts adjacent to mineralizing surfaces are ~4-fold higher than in control bone, whereas osteoclasts adjacent to non-mineralizing surfaces are not significantly altered

abnormal femur morphology ( J:210366 )

• X-ray analysis of femora showed signs of spontaneous fractures, thinned cortical bone, increased amounts of trabecular bone and, in some cases, flaring of the distal femur in tamoxifen-treated mice

• ~2/3 of distal femora exhibit some degree of flaring

decreased femur compact bone thickness ( J:210366 )

• femora of tamoxifen-treated mice exhibit highly thinned cortical bone

• m-CT analysis of femoral diaphyses showed a significantly smaller total volume (TV) and bone volume (BV), confirming that cortical bone in this region is thinner in tamoxifen-treated mice than in controls

abnormal trochanter morphology ( J:210366 )

• enlargement of the third trochanter, the attachment site for the ascending tendon of the gluteus maximus muscle, is noted in tamoxifen-treated mice at 17 weeks of age

short femur ( J:210366 )

• at 17 weeks of age, tamoxifen-treated mice show a 5% reduction in femur length

femur fracture ( J:210366 )

• X-ray analysis of femora showed signs of spontaneous fractures

abnormal tibia morphology ( J:210366 )

• flaring of the proximal tibia is observed in some tamoxifen-treated mice

abnormal tendon collagen fibril morphology ( J:210366 )

• tamoxifen-treated mice show a general shift toward larger diameter collagen fibrils in tendon

• increase in tendon fibril diameter is consistent with a significant decrease in fibril density

• however, no barb-like projections are detected on collagen fibril surfaces in tendons or bone

abnormal long bone diaphysis morphology ( J:210366 )

• microcomputed tomography (m-CT) analysis of femoral diaphyses in tamoxifen-treated mice showed that cortical bone has decreased total volume (TV) and bone volume (BV), increased porosity (BV/TV ratio) and reduced tissue mineral density (TMD), relative to controls

increased width of hypertrophic chondrocyte zone ( J:210366 )

• growth plates of tamoxifen-treated mice display mildly expanded cartilage zones

disorganized long bone epiphyseal plate ( J:210366 )

• H&E staining of femora revealed that growth plates of tamoxifen-treated mice display a mild disorganization in vertical columns

increased long bone epiphyseal plate size ( J:210366 )

• H&E staining of femora revealed that growth plates of tamoxifen-treated mice are relatively wider than in controls

abnormal long bone metaphysis morphology ( J:210366 )

• m-CT analysis of femoral metaphyses in tamoxifen-treated mice showed that trabecular bone exhibits lowered BV, BV/TV ratio, reduced trabecular bone number and increased tracecular spacing, but no significant difference in trabecular thickness or TV relative to controls

abnormal pelvic girdle bone morphology ( J:210366 )

• a 90 degree distortion of the pelvis is noted in tamoxifen-treated mice at 17 weeks of age

rib fractures ( J:210366 )

• at 17 weeks of age, tamoxifen-treated mice exhibit calluses on their ribs; some calluses contain cartilaginous cores, apparently marking sites of healing of spontaneous rib fractures

kyphosis ( J:210366 )

• tamoxifen-treated mice exhibit pronounced kyphosis at 4 months of age

• kyphosis becomes even more severe at 6 months of age

abnormal bone marrow morphology ( J:210366 )

• H&E staining of femora revealed that tamoxifen-treated mice have significantly more adipocytes in the marrow than controls

decreased bone mineral density of femur ( J:210366 )

• in tamoxifen-treated mice, femoral cortical bone shows reduced tissue mineral density relative to controls

decreased compact bone volume ( J:210366 )

• m-CT analysis of femoral diaphyses showed a significantly smaller total volume (TV) and bone volume (BV) in tamoxifen-treated mice

abnormal osteoblast cell number ( J:210366 )

• the proportion of active osteoblasts lining labeling surfaces, at which mineral is being deposited, is markedly increased in femurs of tamoxifen-treated mice relative to controls

• in contrast, the proportion of inactive osteoblasts lining non-labeling surfaces is markedly decreased relative to controls

abnormal osteocyte morphology ( J:210366 )

• immunohistochemical staining of cortical femur showed higher levels of MEPE (a marker of both osteoblasts and osteocytes) and E-11 (a marker of early osteocytes), and lower levels of sclerostin (a marker of mature osteocytes) in tamoxifen-treated mice than in controls, suggesting a deficit in osteocyte maturation

• Goldners Masson trichrome staining of cortical bone revealed increased osteoid seams, not present in controls

• at 10 weeks of age, defective osteocyte maturation is accompanied by markedly increased beta-catenin levels, indicating induction of canonical Wnt signaling

abnormal osteocyte dendritic process morphology ( J:210366 )

• FITC staining of femoral cortical areas showed that osteocytes from tamoxifen-treated mice have reduced numbers of dendritic processes relative to control osteocytes

abnormal osteocyte lacuna morphology ( J:210366 )

• SEM analysis revealed a heterogeneous mineral distribution in femoral cortical areas and showed osteocytic lacunae to be fewer, more rounded, less spindle-shaped and larger than in controls, consistent with a maturation defect

decreased bone trabecula number ( J:210366 )

• m-CT analysis of femoral metaphyses revealed reduced trabecular bone number in tamoxifen-treated mice

increased bone trabecular spacing ( J:210366 )

• m-CT analysis of femoral metaphyses revealed increased tracecular spacing in tamoxifen-treated mice

increased trabecular bone mass ( J:210366 )

• X-ray analysis of femora revealed increased amounts of trabecular bone in tamoxifen-treated mice

abnormal enthesis morphology ( J:210366 )

• at 17 weeks of age, tamoxifen-treated mice exhibit bony protuberances on the scapulae, long bones and pelvises that correspond to enlarged entheses, at which tendons and ligaments attach to bone

abnormal osteoid morphology ( J:210366 )

• Goldners Masson trichrome staining of cortical bone revealed increased osteoid seams, not present in controls

abnormal bone mineralization ( J:210366 )

• dynamic histomorphometry of femora revealed significantly increased numbers of osteoblasts depositing mineralizing ECM within the bone of tamoxifen-treated mice than in control bone

osteomalacia ( J:210366 )

increased bone ossification ( J:210366 )

• dynamic histomorphometry revealed significantly increased labeled bone surfaces in the trabecular portion of femurs in tamoxifen-treated mice relative to controls; the bone formation rate is twice that seen in controls

increased bone resorption ( J:210366 )

• tamoxifen-treated mice show remarkably high bone turnover in an attempt to repair/replace inferior bone

decreased femur stiffness ( J:210366 )

• whole femur stiffness is significantly reduced in tamoxifen-treated mice

decreased bone strength ( J:210366 )

• three-point bending analysis of femora revealed that total displacement (total amount of bone deformation prior to fracture) as well as post-yield displacement (a measure of ductility) are markedly reduced, indicating that tamoxifen-treated femora are significantly more brittle than controls

• post-yield displacement (ductility) prior to fracture is almost absent in tamoxifen-treated femora

• analysis of tissue level biomechanics following fracture revealed a lower Young's modulus and post-yield strain, lowered toughness and yield stress, and lower maximum stress capable of causing fracture

decreased femur maximal load ( J:210366 )

• maximum load sustained prior to fracture as well as the energy necessary to fracture femora are significantly reduced, indicating that femurs of tamoxifen-treated mice are more brittle, weaker, and capable of absorbing less energy than controls

decreased femur yield load ( J:210366 )

• femur yield load (the force necessary to cause permanent bone damage) is significantly reduced in tamoxifen-treated mice

decreased energy dissipated prior to femur fracture ( J:210366 )

• the energy necessary to fracture femora is significantly reduced in tamoxifen-treated mice

fragile skeleton ( J:210366 )

• at 17 weeks of age, tamoxifen-treated mice exhibit spontaneous fractures and enlarged entheses due to substantially weakened bone, with no contribution from enlargement or strengthening of skeletal muscle

limbs/digits/tail

abnormal femur morphology ( J:210366 )

• X-ray analysis of femora showed signs of spontaneous fractures, thinned cortical bone, increased amounts of trabecular bone and, in some cases, flaring of the distal femur in tamoxifen-treated mice

• ~2/3 of distal femora exhibit some degree of flaring

decreased femur compact bone thickness ( J:210366 )

• femora of tamoxifen-treated mice exhibit highly thinned cortical bone

• m-CT analysis of femoral diaphyses showed a significantly smaller total volume (TV) and bone volume (BV), confirming that cortical bone in this region is thinner in tamoxifen-treated mice than in controls

abnormal trochanter morphology ( J:210366 )

• enlargement of the third trochanter, the attachment site for the ascending tendon of the gluteus maximus muscle, is noted in tamoxifen-treated mice at 17 weeks of age

short femur ( J:210366 )

• at 17 weeks of age, tamoxifen-treated mice show a 5% reduction in femur length

femur fracture ( J:210366 )

• X-ray analysis of femora showed signs of spontaneous fractures

abnormal tibia morphology ( J:210366 )

• flaring of the proximal tibia is observed in some tamoxifen-treated mice

muscle

abnormal tendon collagen fibril morphology ( J:210366 )

• tamoxifen-treated mice show a general shift toward larger diameter collagen fibrils in tendon

• increase in tendon fibril diameter is consistent with a significant decrease in fibril density

• however, no barb-like projections are detected on collagen fibril surfaces in tendons or bone

adipose tissue

decreased gonadal fat pad weight ( J:210366 )

• after tamoxifen treatment, both sexes show a significant reduction in gonadal fad pad weight at 17 weeks of age

decreased inguinal fat pad weight ( J:210366 )

• after tamoxifen treatment, both sexes show a significant reduction in inguinal fad pad weight at 17 weeks of age

hematopoietic system

increased osteoclast cell number ( J:210366 )

• TRAP staining revealed a sharp increase in numbers of osteoclasts lining bone surfaces in both trabecular and cortical bone of femurs in tamoxifen-treated mice relative to controls

• osteoclasts adjacent to mineralizing surfaces are ~4-fold higher than in control bone, whereas osteoclasts adjacent to non-mineralizing surfaces are not significantly altered

immune system

increased osteoclast cell number ( J:210366 )

• TRAP staining revealed a sharp increase in numbers of osteoclasts lining bone surfaces in both trabecular and cortical bone of femurs in tamoxifen-treated mice relative to controls

• osteoclasts adjacent to mineralizing surfaces are ~4-fold higher than in control bone, whereas osteoclasts adjacent to non-mineralizing surfaces are not significantly altered

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:210366 )

N • at 17 weeks of age, tamoxifen-treated mice are not rachitic and show no significant differences in serum phosphate or serum ionized calcium levels relative to controls

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
osteogenesis imperfecta		DOID:12347	OMIM:PS166200	J:210366