Calcified Tissue International

, Volume 94, Issue 6, pp 621–631 | Cite as

Type III Collagen Regulates Osteoblastogenesis and the Quantity of Trabecular Bone

  • Susan W. VolkEmail author
  • Shalin R. Shah
  • Arthur J. Cohen
  • Yanjian Wang
  • Becky K. Brisson
  • Laurie K. Vogel
  • Kurt D. Hankenson
  • Sherrill L. Adams
Original Research


Type III collagen (Col3), a fibril-forming collagen, is a major extracellular matrix component in a variety of internal organs and skin. It is also expressed at high levels during embryonic skeletal development and is expressed by osteoblasts in mature bone. Loss of function mutations in the gene encoding Col3 (Col3a1) are associated with vascular Ehlers–Danlos syndrome (EDS). Although the most significant clinical consequences of this syndrome are associated with catastrophic failure and impaired healing of soft tissues, several studies have documented skeletal abnormalities in vascular EDS patients. However, there are no reports of the role of Col3 deficiency on the murine skeleton. We compared craniofacial and skeletal phenotypes in young (6–8 weeks) and middle-aged (>1 year) control (Col3+/+) and haploinsufficient (Col3+/−) mice, as well as young null (Col3−/−) mice by microcomputed tomography (μCT). Although Col3+/− mice did not have significant craniofacial abnormalities based upon cranial morphometrics, μCT analysis of distal femur trabecular bone demonstrated significant reductions in bone volume (BV), bone volume fraction (BV/TV), connectivity density, structure model index and trabecular thickness in young adult female Col3+/− mice relative to wild-type littermates. The reduction in BV/TV persisted in female mice at 1 year of age. Next, we evaluated the role of Col3 in vitro. Osteogenesis assays revealed that cultures of mesenchymal progenitors collected from Col3−/− embryos display decreased alkaline phosphatase activity and reduced capacity to undergo mineralization. Consistent with this data, a reduction in expression of osteogenic markers (type I collagen, osteocalcin and bone sialoprotein) correlates with reduced bone Col3 expression in Col3+/− mice and with age in vivo. A small but significant reduction in osteoclast numbers was found in Col3+/− compared to Col3+/+ bones. Taken together, these findings indicate that Col3 plays a role in development of trabecular bone through its effects on osteoblast differentiation.


Bone formation Extracellular matrix Mineralization Osteogenesis Osteoporosis Type III collagen 



This work was supported by grants from the University of Pennsylvania Research Foundation and the Penn Center for Musculoskeletal Disorders (SLA and SWV) and the National Institutes of Health (K08AR053945 to SWV and RO1 AR044692 to SLA).


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Susan W. Volk
    • 1
    • 2
    Email author
  • Shalin R. Shah
    • 3
    • 4
  • Arthur J. Cohen
    • 3
  • Yanjian Wang
    • 1
  • Becky K. Brisson
    • 1
  • Laurie K. Vogel
    • 1
  • Kurt D. Hankenson
    • 5
    • 6
  • Sherrill L. Adams
    • 3
  1. 1.Department of Clinical Studies-PhiladelphiaUniversity of Pennsylvania School of Veterinary MedicinePhiladelphiaUSA
  2. 2.Department of Animal BiologyUniversity of Pennsylvania School of Veterinary MedicinePhiladelphiaUSA
  3. 3.Department of Biochemistry, School of Dental MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  4. 4.Department of Orthodontics, School of Dental MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  5. 5.Department of Clinical Studies-New Bolton Center, School of Veterinary MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  6. 6.Department of Orthopaedic Surgery, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA

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