Table 1.

Type of Study	Model	Type of Blocker	Administration Protocol	Major Effects of Treatment	Reference
Pain Assessment only	Destabilization of the medial meniscus (DMM) surgery in wild-type mice	human soluble receptor to NGF (TrkAd5; produced by David Dawbarn, University of	single subcutaneous injection of 2 mg/kg either the day before surgery or 16 weeks after surgery	Treatment before surgery prevented the development of weight-bearing asymmetry through day 3 post surgery Treatment 16 weeks after surgery reversed weight-bearing asymmetry days 1-3 post treatment Joint histology was not performed	McNamee 2010 [19]
	Rat MIA (1 mg, unilateral)	small molecule inhibitor of TrkA (GZ389988)	single intra-articular injection on day 7 after MIA induction into the ipsilateral joint (dose not stated)	Treatment on day 7 decreased weight-bearing asymmetry for 4 weeks As a control, a subset of rats received an injection into the contralateral knee instead, which had no effect on ipsilateral joint pain Joint histology was not performed	Flannery 2015 [20]
	Rat MIA (3 mg, bilateral)	anti-NGF mAb (derived from monoclonal antibody (mAb) variable domains extracted from the patent application WO 2004/058184 A2 (applicant: Rinat Neuroscience Corporation))	9 mg/kg, s.c., given day 2 after MIA induction	Treatment on day 2 reversed burrowing deficit on day 3 compared to saline Joint histology was not performed	Bryden 2015 [21]
	DMM surgery in PKC δ null mice	anti-NGF-2.5S antibody (Sigma, St. Louis, MO)	30μg, intra-articular, given twice weekly from week 2 to week 8 post-DMM surgery	Treatment decreased mechanical allodynia of the hind paw from week 3 to week 8 compared to saline-injected controls Wild-type mice were not tested Joint histology was not performed	Kc 2016 [22]
Pain and Joint Assessment	Rat MIA (1 mg, right knee)	anti-NGF antibody (AS2886401-00, human IgG1)	one injection (0.1, 0.3 or 1 mg/kg, i.v.)	Treatment on day 3 decreases gait imbalances on day 35 after MIA induction (doses 0.3 and 1 mg/kg) compared to saline Treatment on day 3 or day 14 decreased gait changes on day 21; Treatment 1 hr or 24hrs before gait testing on day 21 had no effect. Treatment on day 3 caused increase in knee diameter on day 35; no effect on macroscopic scoring of tibial surface on day 35	Ishikawa 2015 [23]
	Rat transection of the medial meniscus (MNX)	orally active inhibitor of TrkA kinase activity (AR786)	Preventative: 30 mg/kg, orally administered twice daily beginning one day prior to MNX surgery and continuing through day 14 or day 28 after surgery	Rats that received treatment through day 28 were protected from developing weight-bearing asymmetry and mechanical allodynia of the hind paw at all time points through day 28 Rats that received treatment through day 14 continued to be protected from weight-bearing asymmetry on days 15, 17, and 21 and from mechanical allodynia of the hind paw on day 17; these rats developed both behavioral changes by day 28 No statistically significant effect on macroscopic chondropathy or histological synovitis score by day 28, but trend toward increase in both protocols	Nwosu 2016 [24]
	Rat MIA (1 mg, unilateral) or rat transection of the medial meniscus (MNX)	orally active inhibitor of TrkA kinase activity (AR786)	Therapeutic: 30 mg/kg, orally administered twice daily from day 14 to day 21 after MIA induction or MNX surgery	Treatment decreased weight-bearing asymmetry on day 17 and day 21 in MIA and on day 19 and day 21 after MNX Treatment decreased mechanical allodynia of the hind paw days 19 and 21 for both MIA and MNX In MIA model, treatment caused a statistically significant reduction in histological synovitis score and a trend toward a decrease in macroscopic chondropathy and histological cartilage degeneration and subchondral bone scores by day 21 In MNX model, no effect on macroscopic chondropathy or histological cartilage degeneration scores, but trend toward decreased knee swelling and increased histological subchondral bone score by day 21	Nwosu 2016 [24]
	Rat medial meniscal tear (MMT) (right knee)	humanized anti-NGF mAb (tanezumab)	Preventative (0.1, 1, or 10 mg/kg, s.c., weekly from day of surgery through day 28 after surgery)	Gait deficiency in MMT rats administered vehicle or isotype control (IgG2a) peaked 3 days after surgery, continued through day 7 and resolved by days 14–28 Tanezumab protected against gait deficiency at all time points Increased tibial cartilage degeneration at days 7, 14, 28 for all doses of Tanezumab compared to isotype controls Increased subchondral bone sclerosis at days 7, 14, 28 for all doses Increased tibial osteophytes by day 28 for all doses Adverse Effects: Focal areas of alopecia along the mouth/muzzle began developing on day 14 and were seen in most animals in the 1 mg/kg tanezumab group by day 28.	LaBranche 2016 [25]
	Rat MMT (right knee)	humanized anti-NGF mAb (tanezumab)	Therapeutic (0.1 mg/kg, s.c., days 23 and 30 after surgery)	Increased tibial cartilage degeneration on day 37	LaBranche 2016 [25]
	Rat MMT (right knee)	humanized anti-NGF mAb (tanezumab)	Therapeutic (0.1 mg/kg, s.c., days 57 and 64 after surgery)	No statistically significant increase in tibial cartilage degeneration on day 71	LaBranche 2016 [25]
	Rat MIA (1 mg, left knee)	anti-NGF mAb (muMab 911, mouse monoclonal antibody against hNGF)	Preventative (10 mg/kg, s.c., weekly from the day of MIA induction)	Prevented weight-bearing asymmetry through day 28 compared to saline Alleviated mechanical allodynia of the hindpaw at day 28 only Trend in increased cartilage damage and synovitis by day 28 Decreased number of TRAP positive osteoclasts in tibial plateau by day 28 Adverse Effects: From Day 12 onwards of the preventative muMab 911, some rats exhibited skin irritation Isotype control (IgG1) had no effect on weight-bearing asymmetry or mechanical allodynia compared to vehicle	Xu 2016 [26]
	Rat MIA (1 mg, left knee)	anti-NGF mAb (muMab 911, mouse monoclonal antibody against hNGF)	Therapeutic (10 mg/kg, s.c., days 14 and 21 after MIA induction)	Decreased weight-bearing asymmetry at day 28 Decreased mechanical allodynia at day 21 On average, no change in cartilage damage, but half the rats had less cartilage damage and half the rats had more cartilage damage than the rats in the vehicle group No change in synovitis by day 28 Decreased number of TRAP positive osteoclasts in tibial plateau by day 28	Xu 2016 [26]
Veterinary pilot study	Randomized, parallel group, stratified, double masked, placebo controlled, proof of principle clinical pilot study design; dogs with degenerative joint disease and mobility	canine-specific anti-NGF mAb (NV-01)	Single dose of 200 μg/kg of a 2 mg/ml solution administered IV over a 1-minute period through an intra-venous 20G catheter	Improvement in owner assessment criteria days 14 and 28 compared to placebo (saline) Other outcome measures had overall improvements in the treatment group but not in the placebo group, altough there were not statistically signficant differences at any one time point No adverse events over 4-week period	Lascelles 2015 [27]
	Placebo-controlled, pilot, masked clinical study; cats with degenerative joint disease and mobility impairment	fully felinized anti-NGF mAb (NV-02)	Single dose of 0.4 or 0.8 mg/kg, s.c.	Improved activity levels in cats for 6 weeks Overall, there was a strong placebo effect, but owner assessments of the treatment group improved at week 3 compared to placebo (saline) No adverse events over 6-week period	Gruen 2016 [28]