TABLE 5.

Selected skeletal phenotypes associated to MMP deficiency in mice.

Genotype	Phenotype	References
Mmp2–/–	MMP-2 knockout (vs. wild-type) mice show: (i) craniofacial defects (such as shorter and broader snouts, hypertelorism, smaller jaws, dome-shaped and taller skulls), (ii) severe arthritis and joint contractures (even in young mice) with articular cartilage destruction and erosion of the underlying bone surface, (iii) joint pathology with increased cellular infiltration and proteoglycan depletion in antigen-induced arthritis, (iv) diminished bone integrity (such as long bones with osteopenia, fractured tibiae), (v) anomalous bone development (e.g., reduced number of long bones, decreased femur and tibia length in adult mice, calvarial bones with a greater [48%] thickness by 55 weeks of age, trabecular bone with fewer osteocytes), (vi) progressive decrease in bone mineral density and increase in bone porosity (characterized by e.g., low trabecular connectivity density, reduced mineral-collagen relation, thinner diaphyseal cortex, less nanoindentation modulus), (vii) increased number of empty lacunae as the mice aged (e.g., about 3-fold by 55 weeks of age), (viii) loss of the canalicular network architecture in calvariae and slighter in long bones, and (ix) presumably expression of bone sialoprotein (which increases osteoblast differentiation and activity) and osteopontin (which increases osteoclast activity).	Inoue et al., 2006; Mosig et al., 2007; Lieu et al., 2011; Nyman et al., 2011; Madsen et al., 2013
Mmp9–/–	MMP-9 knockout (vs. wild-type) mice show: (i) long bones (e.g., metatarsals) with increased (e.g., 4-8-fold for 3 weeks old mice) hypertrophic (cartilage) zones, (ii) 10% shorter long bones, which is the only remaining phenotype in older MMP-9 deficient mice, (iii) irregularly shaped bone spicules, (iv) delayed endochondral ossification, (v) expanded zone of hypertrophic chondrocytes in the growth plate, (vi) reduced vascular invasion into the hypertrophic cartilage, (vii) slowed apoptosis of hypertrophic chondrocytes, (viii) impaired osteoclast/condroclast recruitment, (ix) anomalous growth in trabecular bone mass, and (x) improved connectivity density of the tibia trabeculae. This phenotype eventually resolve, resulting in correction of bone growth defects after approximately 4 weeks of age.	Vu et al., 1998; Ortega et al., 2003; Nyman et al., 2011; Kojima et al., 2013
Mmp13–/–	Mmp13–/– (vs. Mmp13±) mice embryos show: (i) progressive changes in the embryonic growth plates (e.g., increased length which persisted in adults), (ii) delayed endochondral ossification, (iii) augmented metaphyseal trabecular bone mass as the mice aged (e.g., 3 months old), (iv) diminished resistance to fracture in long bones, (v) delay in fracture repair, (vi) defective vascular penetration and chondroclast attraction to the fracture callus, (vii) noticeable expression of collagen type X, osteopontin, and VEGF by hypertrophic chondrocytes.	Inada et al., 2001; Inada et al., 2002; Inada et al., 2004; Stickens et al., 2004; Kosaki et al., 2007; Tang et al., 2012; Singh et al., 2013
Mmp14–/–	MMP-14 knockout (vs. wild-type) mice show: (i) progressive disturbances (e.g., smaller body size and weight, very high postnatal mortality), possibly caused by deprived feeding and therefore malnutrition, (ii) craniofacial dysmorphism in surviving mice (e.g., short snout, hypertelorism, dome-shaped skull, orbital protrusions, unclosed cranial sutures), (iii) incomplete cartilage remodeling, (iv) impaired formation of secondary ossification centers in the epiphyses, (v) ankylosis resulting from joints with arthritis and other factors (e.g., greater vascularity of the ligaments and tendons, overgrowth of hypercellular and wrongly vascularized synovial tissue), (vi) augmented bone resorption, (vii) osteopenia, (viii) osteoporosis, (ix) dwarfism, (x) mesenchymal stem cells commitment to chondrogenesis and adipogenesis instead of osteogenesis.	Holmbeck et al., 1999; Zhou et al., 2000; Holmbeck et al., 2003
Mmp16–/–	MMP-16 knockout (vs. wild-type) mice show shorter size associated with reduced viability of mesenchymal cells in bone tissues.	Shi et al., 2008; Loffek et al., 2011

MMP, matrix metalloproteinase; VEGF, vascular endothelial growth factor.