Fractures in Geriatric Mice Show Decreased Callus Expansion and Bone Volume
Background Poor fracture healing in geriatric populations is a significant source of morbidity, mortality, and cost to individuals and society; however, a fundamental biologic understanding of age-dependent healing remains elusive. The development of an aged-based fracture model system would allow f...
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| Veröffentlicht in: | Clinical orthopaedics and related research 2014-11, Vol.472 (11), p.3523-3532 |
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| creator | Lopas, Luke A. Belkin, Nicole S. Mutyaba, Patricia L. Gray, Chancellor F. Hankenson, Kurt D. Ahn, Jaimo |
| description | Background
Poor fracture healing in geriatric populations is a significant source of morbidity, mortality, and cost to individuals and society; however, a fundamental biologic understanding of age-dependent healing remains elusive. The development of an aged-based fracture model system would allow for a mechanistic understanding that could guide future biologic treatments.
Questions/purposes
Using a small animal model of long-bone fracture healing based on chronologic age, we asked how aging affected (1) the amount, density, and proportion of bone formed during healing; (2) the amount of cartilage produced and the progression to bone during healing; (3) the callus structure and timing of the fracture healing; and (4) the behavior of progenitor cells relative to the observed deficiencies of geriatric fracture healing.
Methods
Transverse, traumatic tibial diaphyseal fractures were created in 5-month-old (n = 104; young adult) and 25-month-old (n = 107; which we defined as geriatric, and are approximately equivalent to 70–85 year-old humans) C57BL/6 mice. Fracture calluses were harvested at seven times from 0 to 40 days postfracture for micro-CT analysis (total volume, bone volume, bone volume fraction, connectivity density, structure model index, trabecular number, trabecular thickness, trabecular spacing, total mineral content, bone mineral content, tissue mineral density, bone mineral density, degree of anisotropy, and polar moment of inertia), histomorphometry (total callus area, cartilage area, percent of cartilage, hypertrophic cartilage area, percent of hypertrophic cartilage area, bone and osteoid area, percent of bone and osteoid area), and gene expression quantification (fold change).
Results
The geriatric mice produced a less robust healing response characterized by a pronounced decrease in callus amount (mean total volume at 20 days postfracture, 30.08 ± 11.53 mm
3
versus 43.19 ± 18.39 mm
3
; p = 0.009), density (mean bone mineral density at 20 days postfracture, 171.14 ± 64.20 mg hydroxyapatite [HA]/cm
3
versus 210.79 ± 37.60 mg HA/cm
3
; p = 0.016), and less total cartilage (mean cartilage area at 10 days postfracture, 101,279 ± 46,755 square pixels versus 302,167 ± 137,806 square pixels; p = 0.013) and bone content (mean bone volume at 20 days postfracture, 11.68 ± 3.18 mm
3
versus 22.34 ± 10.59 mm
3
; p |
| doi_str_mv | 10.1007/s11999-014-3829-x |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4182401</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1622606626</sourcerecordid><originalsourceid>FETCH-LOGICAL-c573t-eb26da703513818a0f636caf766302addf48f58658b4402a4514cda66b1d6a493</originalsourceid><addsrcrecordid>eNqFkU1vFSEUhomxsdfqD3BjSNy4Gcvh4wxsTPTa1sYaF37EHeEyTDvNXLiFGb3-e2lu21QT44rAec7LgYeQZ8BeAWPtYQEwxjQMZCM0N832AVmA4roBEPwhWTDGTGM4fN8nj0u5rFshFX9E9rkChq1pF-TDcXZ-mnModIj0JOTBTXnw9OPgA_18kX7Sd8Hn4Ero6NKN41zo0XbjYhlSpC529G2KgX5L47wOT8he78YSnt6sB-Tr8dGX5fvm7NPJ6fLNWeNVK6YmrDh2rmVCgdCgHetRoHd9iygYd13XS90rjUqvpKwHUoH0nUNcQYdOGnFAXu9yN_NqHTof4pTdaDd5WLv8yyY32D8rcbiw5-mHlaC5ZFADXt4E5HQ1hzLZ9VB8GEcXQ5qLBeQcGSLH_6N1UGaQKV7RF3-hl2nOsf5EpRBbYRTTlYId5XMqJYf-bm5g9tqq3Vm11aq9tmq3tef5_QffddxqrADfAaWW4nnI967-Z-pvWdqsig</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1566739508</pqid></control><display><type>article</type><title>Fractures in Geriatric Mice Show Decreased Callus Expansion and Bone Volume</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>SpringerLink Journals - AutoHoldings</source><creator>Lopas, Luke A. ; Belkin, Nicole S. ; Mutyaba, Patricia L. ; Gray, Chancellor F. ; Hankenson, Kurt D. ; Ahn, Jaimo</creator><creatorcontrib>Lopas, Luke A. ; Belkin, Nicole S. ; Mutyaba, Patricia L. ; Gray, Chancellor F. ; Hankenson, Kurt D. ; Ahn, Jaimo</creatorcontrib><description>Background
Poor fracture healing in geriatric populations is a significant source of morbidity, mortality, and cost to individuals and society; however, a fundamental biologic understanding of age-dependent healing remains elusive. The development of an aged-based fracture model system would allow for a mechanistic understanding that could guide future biologic treatments.
Questions/purposes
Using a small animal model of long-bone fracture healing based on chronologic age, we asked how aging affected (1) the amount, density, and proportion of bone formed during healing; (2) the amount of cartilage produced and the progression to bone during healing; (3) the callus structure and timing of the fracture healing; and (4) the behavior of progenitor cells relative to the observed deficiencies of geriatric fracture healing.
Methods
Transverse, traumatic tibial diaphyseal fractures were created in 5-month-old (n = 104; young adult) and 25-month-old (n = 107; which we defined as geriatric, and are approximately equivalent to 70–85 year-old humans) C57BL/6 mice. Fracture calluses were harvested at seven times from 0 to 40 days postfracture for micro-CT analysis (total volume, bone volume, bone volume fraction, connectivity density, structure model index, trabecular number, trabecular thickness, trabecular spacing, total mineral content, bone mineral content, tissue mineral density, bone mineral density, degree of anisotropy, and polar moment of inertia), histomorphometry (total callus area, cartilage area, percent of cartilage, hypertrophic cartilage area, percent of hypertrophic cartilage area, bone and osteoid area, percent of bone and osteoid area), and gene expression quantification (fold change).
Results
The geriatric mice produced a less robust healing response characterized by a pronounced decrease in callus amount (mean total volume at 20 days postfracture, 30.08 ± 11.53 mm
3
versus 43.19 ± 18.39 mm
3
; p = 0.009), density (mean bone mineral density at 20 days postfracture, 171.14 ± 64.20 mg hydroxyapatite [HA]/cm
3
versus 210.79 ± 37.60 mg HA/cm
3
; p = 0.016), and less total cartilage (mean cartilage area at 10 days postfracture, 101,279 ± 46,755 square pixels versus 302,167 ± 137,806 square pixels; p = 0.013) and bone content (mean bone volume at 20 days postfracture, 11.68 ± 3.18 mm
3
versus 22.34 ± 10.59 mm
3
; p < 0.001) compared with the young adult mice. However, the amount of cartilage and bone relative to the total callus size was similar between the adult and geriatric mice (mean bone volume fraction at 25 days postfracture, 0.48 ± 0.10 versus 0.50 ± 0.13; p = 0.793), and the relative expression of chondrogenic (mean fold change in SOX9 at 10 days postfracture, 135 + 25 versus 90 ± 52; p = 0.221) and osteogenic genes (mean fold change in osterix at 20 days postfracture, 22.2 ± 5.3 versus 18.7 ± 5.2; p = 0.324) was similar. Analysis of mesenchymal cell proliferation in the geriatric mice relative to adult mice showed a decrease in proliferation (mean percent of undifferentiated mesenchymal cells staining proliferating cell nuclear antigen [PCNA] positive at 10 days postfracture, 25% ± 6.8% versus 42% ± 14.5%; p = 0.047).
Conclusions
Our findings suggest that the molecular program of fracture healing is intact in geriatric mice, as it is in geriatric humans, but callus expansion is reduced in magnitude.
Clinical Relevance
Our study showed altered healing capacity in a relevant animal model of geriatric fracture healing. The understanding that callus expansion and bone volume are decreased with aging can help guide the development of targeted therapeutics for these difficult to heal fractures.</description><identifier>ISSN: 0009-921X</identifier><identifier>EISSN: 1528-1132</identifier><identifier>DOI: 10.1007/s11999-014-3829-x</identifier><identifier>PMID: 25106797</identifier><language>eng</language><publisher>Boston: Springer US</publisher><subject>Aging - pathology ; Aging - physiology ; Animals ; Basic Research ; Bone and Bones - diagnostic imaging ; Bone and Bones - pathology ; Bone Density - physiology ; Bony Callus - pathology ; Bony Callus - physiology ; Cartilage - physiology ; Conservative Orthopedics ; Disease Models, Animal ; Fracture Healing - physiology ; Fractures, Bone - diagnostic imaging ; Fractures, Bone - pathology ; Fractures, Bone - physiopathology ; Humans ; Imaging, Three-Dimensional ; Male ; Medicine ; Medicine & Public Health ; Mice ; Mice, Inbred C57BL ; Organ Size ; Orthopedics ; Sports Medicine ; Stem Cells - pathology ; Stem Cells - physiology ; Surgery ; Surgical Orthopedics ; X-Ray Microtomography</subject><ispartof>Clinical orthopaedics and related research, 2014-11, Vol.472 (11), p.3523-3532</ispartof><rights>The Association of Bone and Joint Surgeons® 2014</rights><rights>The Association of Bone and Joint Surgeons 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c573t-eb26da703513818a0f636caf766302addf48f58658b4402a4514cda66b1d6a493</citedby><cites>FETCH-LOGICAL-c573t-eb26da703513818a0f636caf766302addf48f58658b4402a4514cda66b1d6a493</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182401/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182401/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,41464,42533,51294,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25106797$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lopas, Luke A.</creatorcontrib><creatorcontrib>Belkin, Nicole S.</creatorcontrib><creatorcontrib>Mutyaba, Patricia L.</creatorcontrib><creatorcontrib>Gray, Chancellor F.</creatorcontrib><creatorcontrib>Hankenson, Kurt D.</creatorcontrib><creatorcontrib>Ahn, Jaimo</creatorcontrib><title>Fractures in Geriatric Mice Show Decreased Callus Expansion and Bone Volume</title><title>Clinical orthopaedics and related research</title><addtitle>Clin Orthop Relat Res</addtitle><addtitle>Clin Orthop Relat Res</addtitle><description>Background
Poor fracture healing in geriatric populations is a significant source of morbidity, mortality, and cost to individuals and society; however, a fundamental biologic understanding of age-dependent healing remains elusive. The development of an aged-based fracture model system would allow for a mechanistic understanding that could guide future biologic treatments.
Questions/purposes
Using a small animal model of long-bone fracture healing based on chronologic age, we asked how aging affected (1) the amount, density, and proportion of bone formed during healing; (2) the amount of cartilage produced and the progression to bone during healing; (3) the callus structure and timing of the fracture healing; and (4) the behavior of progenitor cells relative to the observed deficiencies of geriatric fracture healing.
Methods
Transverse, traumatic tibial diaphyseal fractures were created in 5-month-old (n = 104; young adult) and 25-month-old (n = 107; which we defined as geriatric, and are approximately equivalent to 70–85 year-old humans) C57BL/6 mice. Fracture calluses were harvested at seven times from 0 to 40 days postfracture for micro-CT analysis (total volume, bone volume, bone volume fraction, connectivity density, structure model index, trabecular number, trabecular thickness, trabecular spacing, total mineral content, bone mineral content, tissue mineral density, bone mineral density, degree of anisotropy, and polar moment of inertia), histomorphometry (total callus area, cartilage area, percent of cartilage, hypertrophic cartilage area, percent of hypertrophic cartilage area, bone and osteoid area, percent of bone and osteoid area), and gene expression quantification (fold change).
Results
The geriatric mice produced a less robust healing response characterized by a pronounced decrease in callus amount (mean total volume at 20 days postfracture, 30.08 ± 11.53 mm
3
versus 43.19 ± 18.39 mm
3
; p = 0.009), density (mean bone mineral density at 20 days postfracture, 171.14 ± 64.20 mg hydroxyapatite [HA]/cm
3
versus 210.79 ± 37.60 mg HA/cm
3
; p = 0.016), and less total cartilage (mean cartilage area at 10 days postfracture, 101,279 ± 46,755 square pixels versus 302,167 ± 137,806 square pixels; p = 0.013) and bone content (mean bone volume at 20 days postfracture, 11.68 ± 3.18 mm
3
versus 22.34 ± 10.59 mm
3
; p < 0.001) compared with the young adult mice. However, the amount of cartilage and bone relative to the total callus size was similar between the adult and geriatric mice (mean bone volume fraction at 25 days postfracture, 0.48 ± 0.10 versus 0.50 ± 0.13; p = 0.793), and the relative expression of chondrogenic (mean fold change in SOX9 at 10 days postfracture, 135 + 25 versus 90 ± 52; p = 0.221) and osteogenic genes (mean fold change in osterix at 20 days postfracture, 22.2 ± 5.3 versus 18.7 ± 5.2; p = 0.324) was similar. Analysis of mesenchymal cell proliferation in the geriatric mice relative to adult mice showed a decrease in proliferation (mean percent of undifferentiated mesenchymal cells staining proliferating cell nuclear antigen [PCNA] positive at 10 days postfracture, 25% ± 6.8% versus 42% ± 14.5%; p = 0.047).
Conclusions
Our findings suggest that the molecular program of fracture healing is intact in geriatric mice, as it is in geriatric humans, but callus expansion is reduced in magnitude.
Clinical Relevance
Our study showed altered healing capacity in a relevant animal model of geriatric fracture healing. The understanding that callus expansion and bone volume are decreased with aging can help guide the development of targeted therapeutics for these difficult to heal fractures.</description><subject>Aging - pathology</subject><subject>Aging - physiology</subject><subject>Animals</subject><subject>Basic Research</subject><subject>Bone and Bones - diagnostic imaging</subject><subject>Bone and Bones - pathology</subject><subject>Bone Density - physiology</subject><subject>Bony Callus - pathology</subject><subject>Bony Callus - physiology</subject><subject>Cartilage - physiology</subject><subject>Conservative Orthopedics</subject><subject>Disease Models, Animal</subject><subject>Fracture Healing - physiology</subject><subject>Fractures, Bone - diagnostic imaging</subject><subject>Fractures, Bone - pathology</subject><subject>Fractures, Bone - physiopathology</subject><subject>Humans</subject><subject>Imaging, Three-Dimensional</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Organ Size</subject><subject>Orthopedics</subject><subject>Sports Medicine</subject><subject>Stem Cells - pathology</subject><subject>Stem Cells - physiology</subject><subject>Surgery</subject><subject>Surgical Orthopedics</subject><subject>X-Ray Microtomography</subject><issn>0009-921X</issn><issn>1528-1132</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqFkU1vFSEUhomxsdfqD3BjSNy4Gcvh4wxsTPTa1sYaF37EHeEyTDvNXLiFGb3-e2lu21QT44rAec7LgYeQZ8BeAWPtYQEwxjQMZCM0N832AVmA4roBEPwhWTDGTGM4fN8nj0u5rFshFX9E9rkChq1pF-TDcXZ-mnModIj0JOTBTXnw9OPgA_18kX7Sd8Hn4Ero6NKN41zo0XbjYhlSpC529G2KgX5L47wOT8he78YSnt6sB-Tr8dGX5fvm7NPJ6fLNWeNVK6YmrDh2rmVCgdCgHetRoHd9iygYd13XS90rjUqvpKwHUoH0nUNcQYdOGnFAXu9yN_NqHTof4pTdaDd5WLv8yyY32D8rcbiw5-mHlaC5ZFADXt4E5HQ1hzLZ9VB8GEcXQ5qLBeQcGSLH_6N1UGaQKV7RF3-hl2nOsf5EpRBbYRTTlYId5XMqJYf-bm5g9tqq3Vm11aq9tmq3tef5_QffddxqrADfAaWW4nnI967-Z-pvWdqsig</recordid><startdate>20141101</startdate><enddate>20141101</enddate><creator>Lopas, Luke A.</creator><creator>Belkin, Nicole S.</creator><creator>Mutyaba, Patricia L.</creator><creator>Gray, Chancellor F.</creator><creator>Hankenson, Kurt D.</creator><creator>Ahn, Jaimo</creator><general>Springer US</general><general>Lippincott Williams & Wilkins Ovid Technologies</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QP</scope><scope>7RV</scope><scope>7T5</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20141101</creationdate><title>Fractures in Geriatric Mice Show Decreased Callus Expansion and Bone Volume</title><author>Lopas, Luke A. ; Belkin, Nicole S. ; Mutyaba, Patricia L. ; Gray, Chancellor F. ; Hankenson, Kurt D. ; Ahn, Jaimo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c573t-eb26da703513818a0f636caf766302addf48f58658b4402a4514cda66b1d6a493</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Aging - pathology</topic><topic>Aging - physiology</topic><topic>Animals</topic><topic>Basic Research</topic><topic>Bone and Bones - diagnostic imaging</topic><topic>Bone and Bones - pathology</topic><topic>Bone Density - physiology</topic><topic>Bony Callus - pathology</topic><topic>Bony Callus - physiology</topic><topic>Cartilage - physiology</topic><topic>Conservative Orthopedics</topic><topic>Disease Models, Animal</topic><topic>Fracture Healing - physiology</topic><topic>Fractures, Bone - diagnostic imaging</topic><topic>Fractures, Bone - pathology</topic><topic>Fractures, Bone - physiopathology</topic><topic>Humans</topic><topic>Imaging, Three-Dimensional</topic><topic>Male</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Organ Size</topic><topic>Orthopedics</topic><topic>Sports Medicine</topic><topic>Stem Cells - pathology</topic><topic>Stem Cells - physiology</topic><topic>Surgery</topic><topic>Surgical Orthopedics</topic><topic>X-Ray Microtomography</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lopas, Luke A.</creatorcontrib><creatorcontrib>Belkin, Nicole S.</creatorcontrib><creatorcontrib>Mutyaba, Patricia L.</creatorcontrib><creatorcontrib>Gray, Chancellor F.</creatorcontrib><creatorcontrib>Hankenson, Kurt D.</creatorcontrib><creatorcontrib>Ahn, Jaimo</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Immunology Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Clinical orthopaedics and related research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lopas, Luke A.</au><au>Belkin, Nicole S.</au><au>Mutyaba, Patricia L.</au><au>Gray, Chancellor F.</au><au>Hankenson, Kurt D.</au><au>Ahn, Jaimo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Fractures in Geriatric Mice Show Decreased Callus Expansion and Bone Volume</atitle><jtitle>Clinical orthopaedics and related research</jtitle><stitle>Clin Orthop Relat Res</stitle><addtitle>Clin Orthop Relat Res</addtitle><date>2014-11-01</date><risdate>2014</risdate><volume>472</volume><issue>11</issue><spage>3523</spage><epage>3532</epage><pages>3523-3532</pages><issn>0009-921X</issn><eissn>1528-1132</eissn><abstract>Background
Poor fracture healing in geriatric populations is a significant source of morbidity, mortality, and cost to individuals and society; however, a fundamental biologic understanding of age-dependent healing remains elusive. The development of an aged-based fracture model system would allow for a mechanistic understanding that could guide future biologic treatments.
Questions/purposes
Using a small animal model of long-bone fracture healing based on chronologic age, we asked how aging affected (1) the amount, density, and proportion of bone formed during healing; (2) the amount of cartilage produced and the progression to bone during healing; (3) the callus structure and timing of the fracture healing; and (4) the behavior of progenitor cells relative to the observed deficiencies of geriatric fracture healing.
Methods
Transverse, traumatic tibial diaphyseal fractures were created in 5-month-old (n = 104; young adult) and 25-month-old (n = 107; which we defined as geriatric, and are approximately equivalent to 70–85 year-old humans) C57BL/6 mice. Fracture calluses were harvested at seven times from 0 to 40 days postfracture for micro-CT analysis (total volume, bone volume, bone volume fraction, connectivity density, structure model index, trabecular number, trabecular thickness, trabecular spacing, total mineral content, bone mineral content, tissue mineral density, bone mineral density, degree of anisotropy, and polar moment of inertia), histomorphometry (total callus area, cartilage area, percent of cartilage, hypertrophic cartilage area, percent of hypertrophic cartilage area, bone and osteoid area, percent of bone and osteoid area), and gene expression quantification (fold change).
Results
The geriatric mice produced a less robust healing response characterized by a pronounced decrease in callus amount (mean total volume at 20 days postfracture, 30.08 ± 11.53 mm
3
versus 43.19 ± 18.39 mm
3
; p = 0.009), density (mean bone mineral density at 20 days postfracture, 171.14 ± 64.20 mg hydroxyapatite [HA]/cm
3
versus 210.79 ± 37.60 mg HA/cm
3
; p = 0.016), and less total cartilage (mean cartilage area at 10 days postfracture, 101,279 ± 46,755 square pixels versus 302,167 ± 137,806 square pixels; p = 0.013) and bone content (mean bone volume at 20 days postfracture, 11.68 ± 3.18 mm
3
versus 22.34 ± 10.59 mm
3
; p < 0.001) compared with the young adult mice. However, the amount of cartilage and bone relative to the total callus size was similar between the adult and geriatric mice (mean bone volume fraction at 25 days postfracture, 0.48 ± 0.10 versus 0.50 ± 0.13; p = 0.793), and the relative expression of chondrogenic (mean fold change in SOX9 at 10 days postfracture, 135 + 25 versus 90 ± 52; p = 0.221) and osteogenic genes (mean fold change in osterix at 20 days postfracture, 22.2 ± 5.3 versus 18.7 ± 5.2; p = 0.324) was similar. Analysis of mesenchymal cell proliferation in the geriatric mice relative to adult mice showed a decrease in proliferation (mean percent of undifferentiated mesenchymal cells staining proliferating cell nuclear antigen [PCNA] positive at 10 days postfracture, 25% ± 6.8% versus 42% ± 14.5%; p = 0.047).
Conclusions
Our findings suggest that the molecular program of fracture healing is intact in geriatric mice, as it is in geriatric humans, but callus expansion is reduced in magnitude.
Clinical Relevance
Our study showed altered healing capacity in a relevant animal model of geriatric fracture healing. The understanding that callus expansion and bone volume are decreased with aging can help guide the development of targeted therapeutics for these difficult to heal fractures.</abstract><cop>Boston</cop><pub>Springer US</pub><pmid>25106797</pmid><doi>10.1007/s11999-014-3829-x</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | Clinical orthopaedics and related research, 2014-11, Vol.472 (11), p.3523-3532 |
| issn | 0009-921X 1528-1132 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4182401 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; SpringerLink Journals - AutoHoldings |
| subjects | Aging - pathology Aging - physiology Animals Basic Research Bone and Bones - diagnostic imaging Bone and Bones - pathology Bone Density - physiology Bony Callus - pathology Bony Callus - physiology Cartilage - physiology Conservative Orthopedics Disease Models, Animal Fracture Healing - physiology Fractures, Bone - diagnostic imaging Fractures, Bone - pathology Fractures, Bone - physiopathology Humans Imaging, Three-Dimensional Male Medicine Medicine & Public Health Mice Mice, Inbred C57BL Organ Size Orthopedics Sports Medicine Stem Cells - pathology Stem Cells - physiology Surgery Surgical Orthopedics X-Ray Microtomography |
| title | Fractures in Geriatric Mice Show Decreased Callus Expansion and Bone Volume |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-02T20%3A14%3A19IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Fractures%20in%20Geriatric%20Mice%20Show%20Decreased%20Callus%20Expansion%20and%20Bone%20Volume&rft.jtitle=Clinical%20orthopaedics%20and%20related%20research&rft.au=Lopas,%20Luke%20A.&rft.date=2014-11-01&rft.volume=472&rft.issue=11&rft.spage=3523&rft.epage=3532&rft.pages=3523-3532&rft.issn=0009-921X&rft.eissn=1528-1132&rft_id=info:doi/10.1007/s11999-014-3829-x&rft_dat=%3Cproquest_pubme%3E1622606626%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1566739508&rft_id=info:pmid/25106797&rfr_iscdi=true |